CN112040938A - Solid forms of fasoracetam - Google Patents

Abstract

The present disclosure relates to co-crystals of fasorasitan, including R-fasorasitan, and various co-crystal formers. Also provided are crystalline materials comprising fasorasitan, including R-fasorasitan. The present disclosure also includes pharmaceutical compositions and methods of treatment of the co-crystals and crystalline materials of the present disclosure.

Description

Solid forms of fasoracetam

This application claims U.S. provisional application No. 62/619,062 filed on 18/1/2018; us provisional application No. 62/668,092 filed on 7.5.2018; and priority of U.S. provisional application No. 62/683,325 filed on 11/6/2018; all of which are incorporated by reference in their entirety.

Recently, a clinical trial based on precision medicine was completed reporting the successful treatment of Attention Deficit Hyperactivity Disorder (ADHD) in subjects with at least one genetic variation in metabotropic glutamate receptor (mGluR) network genes. In this study, subjects with genetic variation in mGluR network genes were successfully treated with fasorasitan (NFC-1), which was shown in vitro to be a nonselective activator of all classes of mGluRs (see Hirouchi M, et al (2000) European Journal of Pharmacology 387: 9-17; see also WO 2017/044491). Fasorexiptan has also been successful in treating patients with ADHD and 22q11.2 deficiency syndromes (see, e.g., WO2017/044491), patients with anxiety (see, e.g., WO2017/044503), patients with behavioral disorders (see, e.g., WO2017/044502), patients with Tourette's syndrome (see, e.g., WO2017/044497), and is suggested for use in treating anorexia (see, e.g., PCT/US 2017/050228). Fasorasitan can be used orally and is generally prepared in the form of a monohydrate so far. Fasorasitan has a chiral center and the R-enantiomer has been developed clinically as R-fasorasitan monohydrate form I. From a manufacturing perspective, fasorasitan is considered a challenging product due to its low melting point (measured at about 52 ℃ to about 57 ℃). It would be advantageous to use solid forms of fasorasitan having a higher melting point to make manufacture and storage more convenient and robust.

All references disclosed herein are incorporated by reference in their entirety.

Disclosed herein are co-crystals of a crystalline compound comprising fasorasitan and fasorasitan. A co-crystal is a chemical composition of two or more compounds that generally has unique crystallographic and spectroscopic properties compared to the constituent compounds. Unlike salts (which have a neutral net charge but are composed of charge balancing components), co-crystals, while also having a neutral net charge, are composed of neutral components. Thus, unlike salts, the stoichiometry of the co-crystal cannot be determined based on charge balance. In practice, one can often obtain a molar ratio of the constituent compounds greater than or less than 1: 1. The molar ratio of the constituent compounds is a generally unpredictable characteristic of the co-crystal. Both the salt and the co-crystal are crystalline compounds containing more than one component.

Co-crystals have the potential to alter physicochemical properties. More specifically, it has been reported that co-crystals may alter water solubility and/or dissolution rate, improve the stability of relative humidity, and/or improve the bioavailability of the active pharmaceutical ingredient relative to other co-crystals of such ingredients. This property is often unpredictable. For example, the melting temperature of the eutectic is an unpredictable property. The melting point of the co-crystal may be lower, higher or between the melting points of the constituent components. With respect to fasoracetam, particularly R-fasoracetam monohydrate form I, the low melting point of R-fasoracetam monohydrate form I when the temperature is increased can lead to processing problems during tableting or packaging of this form. These problems can be avoided by using solid state forms characterized by higher melting temperatures, such as many of the co-crystals of the present disclosure.

The co-crystals may also be polymorphic in that the co-crystals may exist in one or more different polymorphs. A compound (e.g. a co-crystal) is polymorphic if it has two or more crystal structures, each of which is a polymorph of the compound (or co-crystal).

Various spectroscopic and crystallographic techniques can be used to characterize the co-crystal. These techniques include XRPD, single crystal X-ray, raman spectroscopy, infrared spectroscopy, solid state NMR spectroscopy, and the like. The co-crystals also typically exhibit significant thermal properties. Thermal properties can be analyzed by techniques such as capillary melting point, thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC). These techniques can be used to identify and characterize the co-crystals.

Disclosure of Invention

In various aspects of the disclosure, co-crystals are provided comprising fasorasitan and a compound, wherein the compound comprises a compound selected from-NH₂、-NO₂An alkyl group or a moiety containing a carbonyl moiety, and the compound is not tartaric acid; also provided are co-crystals of fasorasitan and an organic co-crystal former (coformer), wherein the co-crystal former is not tartaric acid.

In other aspects of the disclosure, co-crystals of fasorasitan and an aromatic compound and co-crystals of R-fasorasitan and an aromatic compound are provided.

In other aspects of the disclosure, crystalline compounds comprising fasorasiracetam and an aromatic compound are provided, and crystalline compounds comprising R-fasorasiracetam and an aromatic compound are provided.

In other aspects of the disclosure, a co-crystal of fasoracetam and urea, a co-crystal of fasoracetam and 4-aminobenzoic acid, a co-crystal of fasoracetam and trimesic acid, a co-crystal of fasoracetam and methyl-3, 4, 5-trihydroxybenzoate, a co-crystal of fasoracetam and ethyl gallate, a co-crystal of fasoracetam and phthalic acid, a co-crystal of fasoracetam and 6-hydroxy-2-naphthoic acid, a co-crystal of fasoracetam and 4-nitrobenzoic acid, and a co-crystal of fasoracetam and 2-indole-3-acetic acid are provided.

In other aspects of the disclosure, a co-crystal of R-fasoracetam and urea (including type A and type B of the co-crystal of R-fasoracetam and urea), a co-crystal of R-fasoracetam and 4-aminobenzoic acid, a co-crystal of R-fasoracetam and trimesic acid, a co-crystal of R-fasoracetam and R-ibuprofen, a co-crystal of R-fasoracetam and methyl-3, 4, 5-trihydroxybenzoate, the pharmaceutical composition comprises a eutectic of R-fasoracetam and ethyl gallate, a eutectic of R-fasoracetam and phthalic acid, a eutectic of R-fasoracetam and 6-hydroxy-2-naphthoic acid, a eutectic of R-fasoracetam and 4-nitrobenzoic acid, and a eutectic of R-fasoracetam and 2-indole-3-acetic acid.

In further aspects of the disclosure, crystalline compounds comprising fasorracetam and urea, crystalline compounds comprising fasorracetam and 4-aminobenzoic acid, crystalline compounds comprising fasorracetam and trimesic acid, crystalline compounds comprising fasorracetam and methyl-3, 4, 5-trihydroxybenzoate, crystalline compounds comprising fasorracetam and ethyl gallate, crystalline compounds comprising fasorracetam and phthalic acid, crystalline compounds comprising fasorafeptan and 6-hydroxy-2-naphthoic acid, crystalline compounds comprising fasorafeptan and 4-nitrobenzoic acid, and crystalline compounds comprising fasorracetam and 2-indole-3-acetic acid are provided.

In other aspects of the disclosure, crystalline compounds comprising R-fasoracetam and urea, crystalline compounds comprising R-fasoracetam and 4-aminobenzoic acid, crystalline compounds comprising R-fasoracetam and trimesic acid, crystalline compounds comprising R-fasoracetam and R-ibuprofen, crystalline compounds comprising R-fasoracetam and methyl-3, 4, 5-trihydroxybenzoate, crystalline compounds comprising R-fasoracetam and ethyl gallate, crystalline compounds comprising R-fasoracetam and phthalic acid, crystalline compounds comprising R-fasoracetam and 6-hydroxy-2-naphthoic acid, crystalline compounds comprising R-fasoracetam and 4-nitrobenzoic acid, and crystalline compounds comprising R-fasoracetam and 2-indole-3-ethylbenzoate are provided A crystalline compound of an acid.

In other aspects of the disclosure, pharmaceutical compositions comprising co-crystals or crystalline compounds of fasoracetam are disclosed.

In other aspects of the disclosure, methods and uses are provided for treating human diseases such as ADHD, 22q11.2 deficiency syndrome, anxiety, conduct disorder, Tourette's syndrome, and anorexia with an effective amount of a co-crystal of fasoracetam, a crystalline compound, and/or a pharmaceutical composition comprising the co-crystal and/or the crystalline compound of the disclosure.

In another aspect, there is provided a method for preparing R-fasorasitan form B: a process for co-crystallizing urea, the process comprising mixing R-fasoracetam with urea in a suitable solvent to form a solution, wherein the molar amount of urea to R-fasoracetam is from about 0.7 to about 1.2, and cooling the solution to form R-fasoracetam: urea type B co-crystals.

Definition of

"2-indol-3-acetic acid" refers to indole-3-acetic acid, commonly referred to as 2- (1H-indol-3-yl) acetic acid or 2- (1H-indol-3-yl) acetic acid.

"Anhydrous form" refers to the anhydrous form of R-fasorasitan.

"cocrystal former" in a pharmaceutical cocrystal refers to one or more compounds other than the active ingredient. For example, for a co-crystal of R-fasoracetam made herein, the co-crystal former is a molecule in the co-crystal other than R-fasoracetam. Examples include urea, PABA, R-ibuprofen, and the like. In contrast to R-fasorasitan and the co-crystal former, the co-crystal may also contain a stoichiometric amount of water, such as a monohydrate or a dihydrate.

As used herein, unless otherwise indicated, "fasorasiracetam" refers to R-fasorasiracetam:

"type A" refers to type A of a co-crystal of R-fasorasitan and urea.

"type B" refers to type B of the eutectic of R-fasorasitan and urea.

"form I" refers to form I R-fasoracetam monohydrate.

"type II" refers to type II R-fasoracetam monohydrate.

"milled crystalline material" refers to material prepared by the milling experiments of the present disclosureCrystallizing the material. Such a material is obtained, for example, when the R-fasoracetam and the co-crystal former are milled in a molar ratio according to the various embodiments. In the examples, the masses of the starting materials used correspond to the stoichiometric molar ratio, with a variability (variabilty) of about +/-10%. In some cases, single crystals were prepared and analyzed separately and the simulated diffraction patterns obtained from these single crystals matched the X-ray powder diffraction pattern of the milled crystalline material, confirming that the milled material had the same crystalline form as the co-crystal made from the single crystal formulation. If a separate figure appears, it may be evidence that the stoichiometry of e.g. the polymorph, hydrate or co-crystal differs from the stoichiometry in the preparation of the single crystal. Even without single crystal data, other techniques (e.g., XRPD and differential scanning calorimetry) can be relied upon to identify the co-crystal. This is strong evidence of eutectic formation when the XRPD patterns of the milled crystalline material differ from the linear combination of the XRPD patterns of the component compounds. In the grinding experiments, use was made of ¹H-NMR experiments were performed to determine whether degradation occurred.

By "match" is meant that the two analytical responses (typically XRPD patterns) are identical within normal expected variability to one of ordinary skill in the art. With respect to matching analysis, x-axis alignment is much more important than y-axis alignment in XRPD patterns due to the preferred orientation of the crystals and particle statistics.

"PABA" refers to p-aminobenzoic acid, also referred to herein as 4-aminobenzoic acid.

"R-fasoracetam Forms Mixture" refers to a physical Mixture of R-fasoracetam monohydrate form I, R-fasoracetam monohydrate form II, and R-fasoracetam anhydrate. For example, such a mixture of fasoracetam forms can be prepared according to example 11.

"synthon" refers to an intermolecular construct that shows intermolecular bonds (e.g., hydrogen bonds) between functional moieties of different compounds within the same co-crystal. For example, for fasorasiracetam (including R-fasorasiracetam), one or two carbonyl groups can hydrogen bond to a moiety (e.g., a carboxylic acid) on the co-crystal former, thereby forming a synthon as shown in formula II or III.

Drawings

FIG. 1 is R-fasorasiracetam: XRPD pattern of PABA co-crystals.

Figure 2 is an XRPD pattern of PABA.

FIG. 3 is R-fasorasiracetam: of co-crystals of PABA¹H-NMR spectrum. The peaks are also provided in table 3A.

FIG. 4 is R-fasorasiracetam: DSC thermogram of PABA co-crystal.

FIG. 5 is a DSC thermogram of PABA.

FIG. 6 is R-fasorasiracetam: TGA thermogram of PABA co-crystal.

FIG. 7 is an XRPD pattern for R-fasoracetam monohydrate form I.

FIG. 8 is a DSC thermogram of R-fasoracetam monohydrate form I.

FIG. 9 is a DSC thermogram of R-fasoracetam monohydrate form I.

FIG. 10 is R-fasorasiracetam: solubility curve of the PABA co-crystal.

FIG. 11 is R-fasorasiracetam: XRPD pattern of seed crystals of PABA co-crystals.

Fig. 12 is an overlay of the following XRPD patterns: (1) r-fasoracetam: simulated XRPD pattern of PABA; (2) r-fasorasiracetam of example 2: XRPD pattern of PABA.

FIG. 13 is R-fasorasiracetam: ORTEP map of PABA co-crystals.

FIG. 14 is the following R-fasorasiracetam: overlay of XRPD patterns of PABA co-crystals: (1) r-fasorasiracetam of example 1: XRPD of PABA co-crystal; (2) r-fasorasiracetam of example 3: simulated XRPD pattern of PABA co-crystals.

FIG. 15 is R-fasorasiracetam: simulated XRPD pattern of PABA co-crystals.

FIG. 16 is an XRPD pattern for R-fasoracetam monohydrate form II.

FIG. 17 is a DSC thermogram of R-fasoracetam monohydrate form II.

Fig. 18 is an overlay of the following XRPD patterns: (1) a simulated XRPD pattern of form II R-fasoracetam monohydrate; (2) a simulated XRPD pattern of form I R-fasoracetam monohydrate; (3) a simulated XRPD pattern of anhydrous R-fasorasitan; (4) XRPD pattern of the mixture of R-fasoracetam monohydrate of type I, R-fasoracetam monohydrate of type II and anhydrous R-fasoracetam.

FIG. 19 is an XRPD pattern for anhydrous R-fasoracetam.

FIG. 20 is a DSC thermogram of a mixture of R-fasoracetam monohydrate form I, R-fasoracetam monohydrate form II, and anhydrous R-fasoracetam.

FIG. 21 is a DSC thermogram of anhydrous R-fasoracetam measured at 10 ℃/minute.

FIG. 22 is R-fasoracetam of example 6: XRPD pattern of PABA co-crystals.

Figure 23 is an overlay of the following XRPD patterns: (1) r-fasoracetam: simulated XRPD pattern of PABA; (2) r-fasorasiracetam of example 6: XRPD pattern of PABA.

FIG. 24 is R-fasoracetam of example 7: XRPD pattern of PABA co-crystals.

Figure 25 is an overlay of the following XRPD patterns: (1) r-fasoracetam: simulated XRPD pattern of PABA; (2) r-fasorasiracetam of example 7: XRPD pattern of PABA.

Fig. 26 is an overlay of the following XRPD patterns: (1) a simulated XRPD pattern of form II R-fasoracetam monohydrate; (2) XRPD pattern of R-fasoracetam monohydrate form II.

FIG. 27 is an ORTEP diagram of R-fasoracetam monohydrate form II.

FIG. 28 is a simulated XRPD pattern for R-fasoracetam monohydrate form II.

FIG. 29 is an ORTEP diagram of anhydrous R-fasoracetam.

FIG. 30 is a simulated XRPD pattern of anhydrous R-fasoracetam.

Figure 31 is an overlay of the following XRPD patterns: (1) a simulated XRPD pattern of anhydrous R-fasorasitan; (2) XRPD pattern of anhydrous R-fasoracetam.

FIG. 32 is an ORTEP diagram of R-fasoracetam monohydrate form I.

FIG. 33 is a simulated XRPD pattern of R-fasoracetam monohydrate form I.

Fig. 34 is an overlay of the following XRPD patterns: (1) an XRPD pattern for form I R-fasoracetam monohydrate; (2) simulated XRPD pattern of form I R-fasoracetam monohydrate.

Figure 35 is an overlay of the following XRPD patterns: (1) type a R-fasorasitan: XRPD pattern of urea co-crystal; (2) XRPD pattern of urea; (3) XRPD pattern of R-fasoracetam form mixture.

FIG. 36 is an ORTEP plot of a co-crystal of R-fasoracetam form B and urea.

FIG. 37 is a simulated XRPD pattern of a co-crystal of R-fasorracetam form B and urea.

Fig. 38 is an overlay of the following XRPD patterns: (1) type B R-fasoracetam: XRPD pattern of urea co-crystal; (2) type B R-fasoracetam: simulated XRPD pattern of urea co-crystals.

Fig. 39 is an overlay of the following XRPD patterns: (1) a simulated XRPD pattern of anhydrous R-fasorasitan; (2) a simulated XRPD pattern of form II R-fasoracetam monohydrate; (3) a simulated XRPD pattern of form I R-fasoracetam monohydrate; (4) type B R-fasoracetam: XRPD pattern of urea co-crystal; (5) type B R-fasoracetam: simulated XRPD pattern of urea co-crystals.

FIG. 40 is a DSC thermogram of R-fasoracetam cocrystal form B.

Figure 41 is an overlay of the following XRPD patterns: (1) type B R-fasoracetam: XRPD pattern of urea co-crystal; (2) type B R-fasoracetam: simulated XRPD pattern of urea co-crystals.

Figure 42 is an overlay of the following XRPD patterns: (1) a simulated XRPD pattern of anhydrous R-fasorasitan; (2) a simulated XRPD pattern of form II R-fasoracetam monohydrate; (3) a simulated XRPD pattern of form I R-fasoracetam monohydrate; (4) type B R-fasoracetam: XRPD pattern of urea co-crystal; (5) type B R-fasoracetam: simulated XRPD pattern of urea co-crystals.

Fig. 43 is an overlay of the following XRPD patterns: (1) an XRPD pattern for form I R-fasoracetam monohydrate; (2) XRPD pattern of urea; (3) r-fasoracetam: XRPD pattern of urea co-crystals.

FIG. 44 is R-fasorasiracetam type A: XRPD pattern of urea co-crystals.

Figure 45 is an XRPD pattern of urea.

FIG. 46 is a representation of dissolved R-fasorasiracetam: of co-crystals of urea¹H-NMR spectrum.

FIG. 47 is R-fasorasiracetam type A: DSC thermogram of urea cocrystal (conversion to form B).

FIG. 48 is a DSC thermogram of urea.

Figure 49 is an overlay of the following XRPD patterns: (1) type a R-fasorasitan: XRPD pattern of urea co-crystal; (2) type B R-fasoracetam: simulated XRPD pattern of urea co-crystals.

Figure 50 is an overlay of the following XRPD patterns: (1) an XRPD pattern for form I R-fasoracetam monohydrate; (2) XRPD pattern of trimesic acid; (3) XRPD pattern of eutectic of R-fasoracetam and trimesic acid.

FIG. 51 is R-fasorasiracetam: XRPD pattern of trimesic acid eutectic.

FIG. 52 is an XRPD pattern for trimesic acid.

FIG. 53 is a representation of dissolved R-fasorasiracetam: eutectic of trimesic acid¹H-NMR spectrum.

FIG. 54 is R-fasorasiracetam: DSC thermogram of trimesic acid eutectic.

FIG. 55 is a DSC thermogram of trimesic acid.

FIG. 56 is R-fasorasiracetam: ORTEP diagram of R-ibuprofen cocrystal.

FIG. 57 is R-fasorasiracetam: simulated XRPD pattern of R-ibuprofen cocrystal.

FIG. 58 is an XRPD pattern for milled R-fasorasiracetam and R-ibuprofen.

Figure 59 is an XRPD pattern of R-ibuprofen.

Figure 60 is an overlay of the following XRPD patterns: (1) an XRPD pattern for milled R-fasorasitan and R-ibuprofen; (2) r-fasoracetam: simulation diagram of R-ibuprofen single crystal.

FIG. 61 is a DSC thermogram of milled R-fasoracetam and R-ibuprofen.

FIG. 62 is a DSC thermogram of R-ibuprofen.

FIG. 63 is R-fasorasiracetam: ORTEP map of phthalic acid co-crystals.

FIG. 64 is R-fasorasiracetam: simulated XRPD pattern of phthalic acid co-crystals.

Figure 65 is an XRPD pattern of phthalic acid.

FIG. 66 is an XRPD pattern of a monohydrate co-crystal of R-fasoracetam and phloroglucinol.

Figure 67 is an XRPD pattern of phloroglucinol.

Figure 68 is an overlay of the following XRPD patterns: (1) an XRPD pattern for form I R-fasoracetam monohydrate; (2) an XRPD pattern of phloroglucinol; (3) XRPD pattern of monohydrate co-crystals of R-fasorasitan and phloroglucinol.

FIG. 69 is a DSC thermogram of a monohydrate co-crystal of R-fasoracetam and phloroglucinol.

FIG. 70 is a DSC thermogram of phloroglucinol.

FIG. 71 is an ORTEP diagram of a monohydrate co-crystal of R-fasorasitan and phloroglucinol.

FIG. 72 is a simulated XRPD pattern of a monohydrate co-crystal of R-fasorasitan and phloroglucinol.

Figure 73 is an overlay of the following XRPD patterns: (1) a simulated XRPD pattern of a monohydrate co-crystal of R-fasorasitan and phloroglucinol; (2) XRPD pattern of monohydrate co-crystals of R-fasorasitan and phloroglucinol.

FIG. 74 is an ORTEP diagram of a monohydrate of R-fasorasitan and methyl-3, 4, 5-trihydroxybenzoate co-crystals.

FIG. 75 is a simulated XRPD pattern of the monohydrate of R-fasorasitan and methyl-3, 4, 5-trihydroxybenzoate co-crystals.

Figure 76 is an overlay of the following XRPD patterns: (1) simulated XRPD patterns of monohydrate of R-fasorasitan and methyl-3, 4, 5-trihydroxybenzoate co-crystals; (2) XRPD pattern of monohydrate of R-fasorasitan and methyl-3, 4, 5-trihydroxybenzoate co-crystal.

FIG. 77 is an XRPD pattern for methyl-3, 4, 5-trihydroxybenzoate.

FIG. 78 is R-fasorasiracetam: 1 part of ethyl gallate: 1 ORTEP map of the cocrystal.

FIG. 79 is R-fasorasiracetam: 1 part of ethyl gallate: 1 co-crystal.

FIG. 80 is a milled crystalline R-fasoracetam: XRPD pattern of mixture of ethyl gallates.

Figure 81 is an overlay of the following XRPD patterns: (1) r-fasoracetam: 1 part of ethyl gallate: 1 simulated XRPD pattern of the co-crystal; (2) milled crystalline R-fasorasitan: XRPD pattern of ethyl gallate.

Figure 82 is an XRPD pattern of ethyl gallate.

FIG. 83 is a milled crystalline R-fasoracetam: DSC thermogram of ethyl gallate.

FIG. 84 is a DSC thermogram of ethyl gallate.

FIG. 85 is 1: 2R-fasorasiracetam: ORTEP diagram of gallic acid ethyl ester eutectic.

FIG. 86 is a 1: 2R-fasoracetam: simulated XRPD pattern of ethyl gallate co-crystals.

Fig. 87 is a dihydrate 1: 2R-fasorasitan: ORTEP diagram of gallic acid ethyl ester eutectic.

Fig. 88 is a 1: 2R-fasorasitan: simulated XRPD pattern of dihydrate of ethyl gallate eutectic.

Fig. 89 is 1: 2R-fasorasitan: XRPD pattern of dihydrate of ethyl gallate co-crystal.

Figure 90 is an overlay of the following XRPD patterns: (1)1: 2R-fasorasitan: simulated XRPD pattern of ethyl gallate eutectic dihydrate; (2)1: 2R-fasorasitan: XRPD pattern of dihydrate of ethyl gallate co-crystal.

FIG. 91 is R-fasorasiracetam: cyclic DSC thermogram of 1:2 eutectic dihydrate of ethyl gallate.

FIG. 92 is R-fasorasiracetam: DSC thermogram of 1:2 eutectic dihydrate of ethyl gallate.

FIG. 93 is an XRPD pattern of milled crystalline R-fasoracetam and 6-hydroxy-2-naphthoic acid.

FIG. 94 is an XRPD pattern for 6-hydroxy-2-naphthoic acid.

Figure 95 is an overlay of the following XRPD patterns: (1) an XRPD pattern for form I R-fasoracetam monohydrate; (2) XRPD pattern of 6-hydroxy-2-naphthoic acid; (3) XRPD pattern of milled crystalline R-fasorasitan and 6-hydroxy-2-naphthoic acid.

FIG. 96 is a graph of milled crystalline R-fasorasitan and 6-hydroxy-2-naphthoic acid¹H-NMR spectrum.

FIG. 97 is a DSC thermogram of milled crystalline R-fasoracetam and 6-hydroxy-2-naphthoic acid.

FIG. 98 is a DSC thermogram of 6-hydroxy-2-naphthoic acid.

FIG. 99 is R-fasorasiracetam: ORTEP diagram of 4-nitrobenzoic acid co-crystals.

FIG. 100 is R-fasorasiracetam: simulated XRPD pattern of 4-nitrobenzoic acid co-crystals.

FIG. 101 is a milled R-fasorasiracetam: XRPD pattern of 4-nitrobenzoic acid.

FIG. 102 is an XRPD pattern for 4-nitrobenzoic acid.

Figure 103 is an overlay of the following XRPD patterns: (1) an XRPD pattern for form I R-fasoracetam monohydrate; (2) XRPD pattern of 4-nitrobenzoic acid; (3) XRPD pattern of a milled mixture of R-fasoracetam and 4-nitrobenzoic acid.

Figure 104 is an overlay of the following XRPD patterns: (1) a simulated diagram of a co-crystal of R-fasoracetam and 4-nitrobenzoic acid; (2) XRPD pattern of a milled mixture of R-fasoracetam and 4-nitrobenzoic acid.

FIG. 105 is a DSC thermogram of a triturated mixture of R-fasorracetam and 4-nitrobenzoic acid.

FIG. 106 is a DSC thermogram of 4-nitrobenzoic acid.

FIG. 107 is an XRPD pattern of milled crystalline R-fasorasiracetam and 2-indole-3-acetic acid.

FIG. 108 is an XRPD pattern for 2-indole-3-acetic acid.

Figure 109 is an overlay of the following XRPD patterns: (1) an XRPD pattern for form I R-fasoracetam monohydrate; (2) an XRPD pattern of 2-indole-3-acetic acid; (3) XRPD patterns of milled crystalline R-fasorasitan and 2-indole-3-acetic acid.

FIG. 110 is a drawing of milled crystalline R-fasorasiracetam and 2-indole-3-acetic acid¹H-NMR spectrum.

FIG. 111 is a DSC thermogram of milled crystalline R-fasoracetam and 2-indole-3-acetic acid.

FIG. 112 is a DSC thermogram of 2-indole-3-acetic acid.

Figure 113 is an XRPD pattern of urea.

Figure 114 is an overlay of the following XRPD patterns: (1) a simulated XRPD pattern of anhydrous R-fasorasitan; (2) a simulated XRPD pattern of form II R-fasoracetam monohydrate; (3) a simulated XRPD pattern of form I R-fasoracetam monohydrate; (4) simulated XRPD pattern of urea; (5) type B R-fasoracetam: simulated XRPD pattern of urea co-crystals.

Figure 115 is an overlay of the following XRPD patterns: (1) form a R-fasorasiracetam of example 15: XRPD pattern of urea co-crystal; (2) form B R-fasorasiracetam of example 34: XRPD pattern of urea co-crystal; (3) XRPD pattern of urea; (4) XRPD pattern of R-fasoracetam form mixture.

FIG. 116 is R-fasoracetam form B of example 34: DSC thermogram of urea cocrystal.

Figure 117 is an overlay of the following XRPD patterns: (1) simulated XRPD pattern of urea; (2) an experimental XRPD pattern of example 34; (3) type B R-fasoracetam: simulated XRPD pattern of urea co-crystals.

FIG. 118 is R-fasorasiracetam type A: XRPD pattern of urea co-crystals.

FIG. 119 is R-fasoracetam form A of example 36: DSC thermogram of urea cocrystal.

FIG. 120 is the R-fasoracetam of example 38: XRPD pattern of urea co-crystals.

FIG. 121 is the R-fasoracetam of example 38: DSC thermogram of urea cocrystal.

Figure 122 is an overlay of the following XRPD patterns: (1) type B R-fasoracetam: simulated XRPD patterns of urea co-crystals; (2) an XRPD pattern of example 36 stored at room temperature ("RT") for 3 days; (3) an XRPD pattern of example 36 stored at room temperature for 2 days; (4) an XRPD pattern of example 36 stored at room temperature for 1 day; (5) the XRPD pattern of example 36; (6) form a R-fasorasiracetam of example 15: XRPD pattern of urea co-crystals.

Figure 123 is an overlay of the following XRPD patterns: (1) type B R-fasoracetam: simulated XRPD patterns of urea co-crystals; (2) an XRPD pattern of example 36 stored at-15 ℃ for 3 days; (3) an XRPD pattern of example 36 stored at-15 ℃ for 2 days; (4) an XRPD pattern of example 36 stored at-15 ℃ for 1 day; (5) the XRPD pattern of example 36; (6) form a R-fasorasiracetam of example 15: XRPD pattern of urea co-crystals.

Figure 124 is a simulated XRPD pattern of urea.

FIG. 125 is R-fasorasiracetam: hydrogen bonding diagram of the PABA co-crystal.

FIG. 126 is R-fasorasiracetam: hydrogen bonding patterns of 4-nitrobenzoic acid co-crystals.

FIG. 127 is R-fasoracetam form B: hydrogen bonding pattern of urea co-crystals.

FIG. 128 is R-fasorasiracetam: hydrogen bonding patterns of phthalic acid co-crystals.

FIG. 129 is R-fasorasiracetam: hydrogen bonding patterns of the monohydrate of the phloroglucinol cocrystal.

FIG. 130 is R-fasorasiracetam: hydrogen bond diagram of monohydrate of methyl-3, 4, 5-trihydroxybenzoate eutectic.

FIG. 131 is R-fasorasiracetam: 1 part of ethyl gallate: 1 eutectic hydrogen bond diagram.

FIG. 132 is R-fasorasiracetam: 1 part of ethyl gallate: 2 hydrogen bonding diagram of the co-crystal.

FIG. 133 is R-fasorasiracetam: hydrogen bond pattern of 1:2 eutectic dihydrate of ethyl gallate.

FIG. 134 is R-fasorasiracetam: hydrogen bond diagram of R-ibuprofen eutectic.

Fig. 135 is a theoretical ternary eutectic phase diagram.

FIG. 136 is R-fasorasiracetam: exemplary crystallization procedure for PABA.

FIG. 137 is R-fasorasiracetam: ternary phase diagram of PABA eutectics.

Description of the invention

Many embodiments of the present disclosure relate to a co-crystal of R-fasoracetam and a co-crystal former. The chemical composition of the co-crystal, evidence of co-crystal formation, and molar relationships between the constituent compounds can be provided by single crystal X-ray analysis. Using the single crystal X-ray protocol, so-called "simulated" X-ray powder diffraction ("XRPD") patterns can also be calculated using techniques well known in the art. Such a simulated plot would show which peaks may appear if the crystal is analyzed in an XRPD instrument. However, it is not always possible to obtain a single crystal having a quality sufficient to obtain a single crystal X-ray solution. Without single crystal data, other techniques may be used to provide such chemical information about the eutectic, including evidence of formation. For example, it can be determined whether a co-crystal has been formed by comparing solid state analytical data of the starting component compounds with corresponding analytical data collected on the co-crystal. Data from the co-crystals will be represented by the analytical response, which is not merely a linear combination of the starting component compounds. For example, XRPD can be used for this comparison, and the XRPD pattern of the co-crystal will be different from that of the physical mixture of the starting materials. The XRPD pattern of the co-crystal will typically have one or more peaks which cannot be obtained by adding the XRPD patterns of the components. Thus, XRPD can be used to distinguish cocrystals from mixtures. In addition, chemical characteristics can be obtained from the characteristics (identity) of the starting component compounds and the solution state NMR spectrum. In addition to the case of using molar milling to prepare the co-crystals, solution state NMR spectroscopy can also be used to identify the molar ratio. In molar milling, the stoichiometric ratios of the component compounds are known, and therefore, NMR spectroscopy is not typically used to verify stoichiometry. However, NMR spectroscopy can be used to determine if grinding causes chemical degradation.

Technical data may characterize the co-crystal in a number of ways. For example, the entire XRPD pattern output from the diffractometer may be used to characterize the co-crystal. However, a smaller subset of such data is also possible and generally applicable for characterizing the co-crystal. For example, a eutectic can be characterized using a set of one or more peaks from such a plot. Indeed, often even a single XRPD peak can be used to characterize the co-crystal. When the co-crystals herein are characterized by "one or more peaks" of the XRPD pattern and such peaks are listed, it is meant that any combination of the listed peaks can be used to characterize the co-crystals. Furthermore, in practice, there are other peaks in the XRPD pattern that do not negate or limit characterization.

Similarly, a subset of the spectral or diffraction data may be used alone or in combination with other analytical data to demonstrate the presence of or characterize the co-crystal. Thermal data may also be used to characterize the eutectic. For example, DSC measurements can be used to characterize the co-crystals. When the DSC measurement of the co-crystal is said to be different from the DSC measurement of the component compounds, the co-crystal can be characterized using the DSC measurement alone, or in combination with other techniques. Typically, this measurement is an endothermic event.

The XRPD pattern is an x-y pattern with the x-axis at 2 θ (diffraction angle) and the y-axis at intensity. The plot contains peaks that can be used to characterize the co-crystal or other solid forms. Peaks are usually expressed and referenced by their position on the x-axis rather than the intensity on the y-axis, since peak intensities can be particularly sensitive to sample angle (see Pharmaceutical Analysis, Lee & Web, pp.255-257 (2003)). Thus, one skilled in the art of pharmacy typically does not use strength to characterize a co-crystal or other solid form.

As with any data measurement, there is variability in X-ray powder diffraction. In addition to the variability in peak intensity, there is variability in peak position on the x-axis. However, this variability can often be taken into account when reporting the position of the peaks for characterization. This variability in peak position along the x-axis comes from a variety of sources. One from sample preparation. Samples of the same crystalline material prepared under different conditions may produce slightly different diffraction patterns. Factors such as particle size, moisture content, solvent content, and orientation may all affect the manner in which a sample diffracts X-rays. Another source of variability comes from instrument parameters. Different X-ray instruments operate with different parameters that may result in slightly different diffraction patterns for the same crystalline eutectic. Likewise, different software packages process X-ray data differently, which also leads to variability. These and other sources of variability are known to those of ordinary skill in the pharmaceutical arts.

Due to this source of variability, X-ray diffraction peaks are typically enumerated using the word "about" before the peak in degrees 2 θ, which, as the case may be, displays the data within 0.1 or 0.2 degrees 2 θ of the peak. All X-ray powder diffraction peaks cited herein are reported with a variability of about 0.2 degrees 2 theta, and are intended to be reported with such variability, whether or not the word "about" is shown herein.

There is also variability in thermal measurements (e.g., DSC) and may also be indicative of sample purity. Melting point, DSC, and thermal microscopy, used alone or in combination with techniques such as X-ray powder diffraction, raman spectroscopy, infrared spectroscopy, or some combination thereof, may be used to characterize the co-crystal. For DSC, the typical measurement variability is about 1 ℃. However, with respect to fasorasitan, the DSC measurements reported herein are within 3 ℃ for fasorasitan-containing materials due to low melting properties and interaction with water.

When a co-crystal screen of a compound is conducted with various potential co-crystal formers, the XRPD pattern of each screening result can be compared to the XRPD patterns of the compound and the co-crystal former. If the resulting XRPD pattern can be described by a linear combination of the XRPD patterns of the compound and the co-crystal former, then no co-crystal formation is indicated. Conversely, if the resulting XRPD pattern cannot be described as a linear combination of the XRPD patterns of the compound and the co-crystal former, e.g. due to the presence of one or more other XRPD peaks, then the XRPD data indicates the presence of a new crystalline phase, possibly due to e.g. co-crystal formation.

The co-crystal characterization does not necessarily use the same data as the screening. For example, a co-crystal, like any other compound, is defined by its structure, and its structure is different from that of the starting constituent compound used to construct it. Thus, for example, even though A, B and a: b all have one or more common XRPD peaks, a: the co-crystal of B is also different from a and different from B, provided that a: the overall diagram of B is not merely a linear combination of the diagrams a and B.

In general, a co-crystal will form when certain intermolecular interactions (e.g., through hydrogen bonds) are formed between compounds (e.g., between R-fasorasitan and a co-crystal former). As evidenced by the various ORTEP plots provided herein, a common synthon that has been identified is a synthon that includes an amide moiety in R-fasorasitan (formula I) and a carboxylic acid moiety from a co-crystal former. The synthon is represented in formula II, where the amide moiety is on the right hand side of the synthon, showing covalent and hydrogen bonds. The synthon of formula II is specific for carboxylic acids. In formula III, another synthon can be seen between the carbonyl group of R-fasorasitan (to the left of the synthon) and a class of moieties in which the intermolecular interactions, like formula II, are through hydrogen bonding. In the synthon, Y can be oxygen, nitrogen -NH or- (O) COR₅Wherein R is₅Selected from substituted or unsubstituted alkyl (e.g. C)₁To C₅Alkyl) or substituted or unsubstituted aryl. In some embodiments, Y is- (O) COR₅Wherein R is₅Selected from substituted or unsubstituted alkyl groups.

In other embodiments, co-crystals of fasorasitan (including R-fasorasitan) are provided, wherein the co-crystal former has a structure selected from-NH₂、-NO₂Or at least one moiety comprising a carbonyl moiety, provided that the co-crystal former is not tartaric acid. Examples of carbonyl-containing moieties include organic acids, esters, and amides. In other embodiments, co-crystals of fasorasitan (including R-fasorasitan) are provided, wherein the co-crystal former is an aromatic co-crystal former that may optionally be substituted. The aromatic compounds may be six-membered rings or have different ring sizes or polycyclic aromatic compounds. One example of a polycyclic aromatic compound is a six-membered ring fused to a five-membered ring, and another example is two or more six-membered rings. As used herein, aromatic includes heteroaromatic, such that the ring atoms may all be carbon, or for example at least one ring carbon may be a different element, such as nitrogen, and the fused ring may be substituted or unsubstituted. In addition, the aromatic co-crystal former may be fused to a non-aromatic cyclic moiety. Examples of such non-aromatic cyclic moieties may be partially saturated when they share a ring atom with the aromatic ring, or may be fully saturated when they are not shared.

The aromatic compound may be optionally substituted regardless of whether the aromatic co-crystal former has a fused ring structure. For example, the aromatic compound may have at least one substituent. Examples of substituents include-OH, -NH₂Alkyl, carbonyl-containing moieties and-NO₂And (4) partial. When the carbonyl-containing moiety is an organic acid moiety, examples of such an organic acid moiety include C₁-C₄Organic acids, e.g. C₁And (4) acid. When containing a carbonyl moietyWhen the moiety is an ester moiety, examples include C₁-C₅An ester moiety.

According to the present disclosure, the aromatic co-crystal former may have two substituents, wherein each substituent is independently selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial. In embodiments having two substituents, the first substituent is an organic acid moiety and the second substituent is selected from the group consisting of-OH, -amine, alkyl, organic acid, ester, and-NO₂And (4) partial. The amine group may be-NH₂And (4) partial. The organic acid moiety may be C₁-C₄An organic acid moiety, such as-COOH. In these and other embodiments, when the first substitution is an organic acid moiety and the second substitution is-NH₂Partially, organic acids and-NH₂Moieties may be, for example, ortho, meta or para to each other.

In some embodiments, the second substituent is-NO ₂Part, and the organic acid moiety may be, for example, -NO₂Partially ortho, meta or para. In such embodiments, the organic acid moiety may be C₁-C₄An organic acid moiety, such as-COOH.

In other embodiments, the second substituent is an-OH moiety, and the organic acid moiety may be, for example, ortho, meta, or para to the-OH moiety. In such embodiments, the organic acid moiety may be C₁-C₄An organic acid moiety, such as-COOH.

In other embodiments, the second substituent is an alkyl moiety, e.g., C₁-C₅The alkyl moiety, and the organic acid moiety may be, for example, ortho, meta, or para to the alkyl moiety. In such embodiments, the organic acid moiety may be C₁-C₄An organic acid moiety, such as-COOH.

In other embodiments, the two substituents are independently an organic acid moiety, e.g., C₁-C₄An organic acid moiety, including but not limited to-COOH. The organic acids may be, for example, ortho, meta or para to each other.

In other embodiments, the second substituent is an ester moiety, e.g., C₁-C₅The ester moiety, and the organic acid moiety may be, for example, ortho, meta, or para with respect to the ester moiety. In such embodiments, the organic acid moiety may be C ₁-C₄Organic acids, such as COOH.

In accordance with the present disclosure, when the aromatic, co-crystal former may have three substituents, wherein each substituent is independently selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial. In some embodiments, each substituent is an-OH moiety, and in other embodiments, only one or two substituents are-OH moieties. In some embodiments, one, two, or all three substituents are organic acid moieties. The organic acid may be, for example, C₁-C₄An organic acid moiety, such as-COOH.

In accordance with the present disclosure, when the aromatic, co-crystal former may have four substituents, wherein each substituent is independently selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial. Examples include where one substituent is an ester, e.g. C₁-C₅Ester moieties, including methyl ester moieties. When one substituent is an ester moiety, in some embodiments, one or two or three other substituents are alcohol moieties, such as an-OH moiety. In many embodiments, at least one substituent is an organic acid moiety, such as-COOH.

According to the present disclosure, the eutectic-former may be non-aromatic and comprise a compound selected from-NH₂、-NO₂、-COOH、-C(＝O)-X、-C(＝O)-OR₁Wherein X is a nitrogen-containing group, and R ₁Is an alkyl group. In some embodiments, alkyl is C₁-C₁₁An alkyl group. In these and other embodiments, the co-crystal former comprises at least one-NH₂Moieties, including wherein the eutectic former comprises two-NH groups₂Some embodiments.

According to the present disclosure, the eutectic-former may be non-aromatic and comprise at least one-C (O) NR₂R₃Moiety wherein R₂And R₃Independently selected from H, alkyl, substituted alkyl and C₁-C₅An alcohol. In some embodiments, the co-crystal former contains one-C (O) NR₂R₃And (4) partial. In these and other embodiments, alkyl and substituted alkyl groups may independently contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 carbons. In certain embodiments, alkyl is C₁₁An alkyl group. Substituted alkyl groups may contain halogen, nitrile moieties, or both, with bromine as the particular halogen. In certain embodiments, the alcohol is C₂An alcohol.

According to the present disclosure, the co-crystal former may be non-aromatic and comprise at least one-c (o) NX moiety, wherein X is ═ N-R₄Wherein R is₄Is a carbonyl containing moiety, such as an amide.

The present disclosure includes multiple co-crystals of fasorasitan. In particular, the present disclosure includes examples of co-crystals of R-fasoracetam with 11 different co-crystal formers. In some examples, a plurality of different co-crystals are prepared with R-fasoracetam and the same co-crystal former. Table 1 lists co-crystal formers that form co-crystals with R-fasoracetam below.

TABLE 1 eutectic structures

Of the 11 eutectic formers exemplified herein, 10 of them are aromatic. The aromatic co-crystal former is substituted with a variety of functional groups including amines, carboxylic acids, alkyl groups, hydroxides, esters, and nitro groups. Some are multiply substituted. The pendant hydrogen-donating groups (e.g., alcohols, amines, carboxylic acids, etc.) are at positions and distances that may be advantageous for co-crystallization with fasorasitan. Tables 2 and 3 summarize the co-crystal formers according to the type of substitution.

TABLE 2 substitution of aromatic Co-crystal formers

# of eutectic former	# substitution
			1	1
5	2
		2	3
2	4

TABLE 3 substitution types of aromatic eutectic formers

Substitution type	# of eutectic former
		-NH2	1
-COOH	6
		-alkyl radical	1
-OH	4
		Esters of (A) with (B) and (C)	2
-NO2	1

In some embodiments of the present disclosure, crystalline fasoracetam 4-aminobenzoic acid is provided, for example a co-crystal of fasoracetam and 4-aminobenzoic acid. In many such embodiments, the fasorasiracetam is R-fasorasiracetam. FIG. 1 is a 1: XRPD pattern of the 1 co-crystal. The diffractogram of fig. 1 differs from the diffractograms of the various components of the co-crystal, i.e. fig. 2 and 7. FIG. 2 is an X-ray powder diffraction pattern of 4-aminobenzoic acid, and FIG. 7 is an X-ray powder diffraction pattern of R-fasoracetam monohydrate form I. The two component compounds were used to prepare a co-crystal whose diffractogram is shown in figure 1, the preparation of which is set out in example 1. The co-crystal showed an XRPD peak at about 6.5 ° 2. Neither figure 2 nor figure 7 has a corresponding peak. The closest peak is one at about 7.3 ° 2 θ in the XRPD pattern of form I R-fasoracetam monohydrate, which is 0.8 ° 2 θ away from 6.5 ° 2 θ in fig. 1, well beyond the typical variability of the XRPD peaks. Thus, the presence of this peak at about 6.5 ° 2 θ confirms that the corresponding crystalline material is not a mixture of form I R-fasoracetam monohydrate and PABA, but rather a distinct crystalline phase. The phase is a co-crystal of R-fasorasiracetam and PABA. The peak at about 6.5 ° 2 θ can also be used to characterize the 1: 1 eutectic crystal.

Solution state of FIG. 3¹The H-NMR spectrum showed a stoichiometric ratio of 1: 1, which is useful for assessing stoichiometry since it is derived from a non-milled formulation. The chemical shifts in FIG. 3 are shown in Table 3A at 1: the corresponding atom numbers identified on the molecular structure of the 1 co-crystal are shown below.

Table 3A-R-fasorasitan: FIG. 3 of PABA co-crystal¹Chemical shift of H-NMR spectrum

Atomic number	δ(ppm)
		4	11.9
3	7.6
		2	6.5
1	5.9
		11	7.6
8	4.5
		7	3.4
9b	2.3
		9a,10b	2.1
10a	1.8
		5,6	1.4-1.6

The single crystal formulation and x-ray analysis described in example 3 further confirmed that the stoichiometry of the co-crystal was 1: 1. fig. 6 provides a thermogravimetric thermogram and fig. 10 provides a solubility curve in ethyl acetate. The solubility of the co-crystal is about three times lower compared to form I R-fasoracetam monohydrate. TGA shows that the co-crystal has thermal stability up to about 200 ℃.

Likewise, in the XRPD pattern of PABA or form I R-fasoracetam monohydrate, none of the XRPD peaks at about 10.5 ° 2 Θ, about 11.3 ° 2 Θ, and about 12.0 ° 2 Θ have a corresponding peak within the typical variability of such XRPD peaks. Thus, any of these XRPD peaks is evidence of formation of a co-crystal rather than a mixture of PABA and R-fasoracetam monohydrate form I. Any one or more of these four peaks (about 6.5 ° 2 θ, about 10.5 ° 2 θ, about 11.3 ° 2 θ, and about 12.0 ° 2 θ) can be used to characterize 1 of R-fasorasitan and PABA: 1 eutectic crystal. Other peaks may also be used to characterize the co-crystal of R-fasorasitan and PABA. Indeed, one or more peaks selected from peaks at about 6.5 ° 2 θ, about 10.5 ° 2 θ, about 11.3 ° 2 θ, about 12.0 ° 2 θ, about 13.4 ° 2 θ, about 13.7 ° 2 θ, about 17.4 ° 2 θ, about 18.1 ° 2 θ, about 18.7 ° 2 θ, about 19.6 ° 2 θ, about 20.6 ° 2 θ, about 21.1 ° 2 θ, about 21.4 ° 2 θ, about 22.8 ° 2 θ, about 23.2 ° 2 θ and about 23.7 ° 2 θ may be used to characterize 1: 1 eutectic crystal. Although some of these peaks cannot be used by themselves to confirm the presence of a co-crystal, for example in screening results, because they have potential corresponding peaks in the XRPD pattern of R-fasoracetam monohydrate form I or PABA, they can be used to characterize 1: co-crystals of 1R-fasorasitan with PABA because the chemical composition of the co-crystals is different from each composition.

1 for R-fasorasiracetam and PABA in example 1: 1 preparation of co-crystal 1: 1 eutectic seed. In some embodiments, such seeds are used in batch preparations. Figure 11 is an XRPD pattern of the seed crystal of example 2. It matches the XRPD pattern of fig. 1, confirming that it is 1: 1 eutectic crystal. In addition, 1: 1 eutectic single crystal. Table 4 of example 3 lists the corresponding single crystal data for the solution. It represents a triclinic unit cell with 2 asymmetric units in the unit cell and shows a molecular stoichiometric ratio of R-fasoracetam to PABA of 1: 1, confirming that the stoichiometric ratio is 1: 1. an ORTEP diagram showing the molecules in the unit cell is given in fig. 13, which shows the molecules of both PABA and R-fasorasitan.

Also provided herein are methods of scaling up a co-crystal of R-fasoracetam and PABA. The design of the amplification process of the eutectic is based on R-Larasetiracetam: consistency of the PABA co-crystal (consistency). As can be seen from the hypothetical system of fig. 135, the dashed line shows that the ratio of API and co-crystal former is 1: 1, in this process, similar to R-fasorasitan: 4-aminobenzoic acid eutectic. In this case, the phase boundary is not crossed when the temperature is lowered. Therefore, a change in temperature does not cause a solid phase transition.

The single crystal structure in this disclosure is represented by the ORTEP diagram and the hydrogen bonding diagram, which help to illustrate the intermolecular interactions of the co-crystals. Thermal ellipsoids represent the probability that an electron around an atom is found within its boundary due to vibration. The hydrogen bond diagram shows the molecule in a rod shape with a dashed line between the hydrogen bond donor and acceptor. Hydrogen bonding interactions are defined based on the following criteria, where "H" is hydrogen and "a" is an acceptor atom; a "donor" is an atom covalently bonded to a hydrogen. First, the H-A distance is less than the sum of the Van der Waals radii of H-A. Second, the donor-H-A angle is greater than 120. Third, the donor must be nitrogen, oxygen, or sulfur, with at least 1 covalently bonded hydrogen. Fourth, a must be nitrogen, oxygen, sulfur, or halogen, with at least 1 available lone electron pair.

In fig. 125, R-fasorasiracetam (two peripheral molecules left, right and three lower row molecules) was mixed with 4-aminobenzoic acid (center) at a ratio of 1: mode 1 forms a eutectic. The 4-aminobenzoic acid molecules form homosynthons (homosynthons) in a head-to-head fashion between their carboxylic acid groups.

Without being bound by theory, it is believed that the amine group of the 4-aminobenzoic acid acts as a hydrogen donor for the carbonyl group on the R-fasoracetam five-membered ring and hydrogen bonds with the bridged carbonyl group on another R-fasoracetam molecule, interconnecting the different layers in the crystal structure. On the other side (upper right corner of fig. 125), the same interconnection occurs between two R-fasoracetam molecules, the bridged carbonyl group acting as hydrogen acceptor and the NH group in the five-membered ring acting as hydrogen donor.

The structure can be further confirmed from the overlay of the two XRPD patterns. In the overlay shown in fig. 12, the simulated XRPD pattern of the single crystal matches the XRPD pattern of the seed crystal of example 2. In the overlay shown in fig. 14, the single crystal simulated XRPD pattern of example 3 is compared to the R-fasorasiracetam of example 1: XRPD pattern matching for PABA formulations. Thus, each of examples 1, 2 and 3 produced a 1: 1 co-crystal of PABA and R-fasoracetam.

The thermal data can be used alone or in combination with other analytical data (e.g., XRPD data) to characterize the 1: 1 eutectic crystal. FIG. 4 is a 1: 1 eutectic DSC thermogram. DSC shows an endothermic event with an onset temperature of about 114 ℃, which can be used to characterize R-fasorasitan with PABA as 1: 1 eutectic crystal. The DSC endotherm is different from PABA and R-fasoracetam monohydrate form I. The PABA endotherm at about 187 deg.C (FIG. 5) and the R-fasoracetam monohydrate form I endotherm at about 52 deg.C (FIG. 8; in FIG. 9, DSC measurements were performed on samples of R-fasoracetam monohydrate form I stored under drier conditions than ambient conditions). DSC also indicates that the co-crystal may have excellent handling and storage properties, since endotherms indicate melting, which is about 60 ℃ higher than the relatively low melting form I R-fasoracetam monohydrate.

A DSC onset temperature of about 114 ℃ can also be used to characterize the 1: 1 eutectic crystal. Specifically, a DSC onset temperature of about 114 ℃ may be used with one or more XRPD peaks selected from peaks at about 6.5 ° 2 θ, about 10.5 ° 2 θ, about 11.3 ° 2 θ, about 12.0 ° 2 θ, about 13.4 ° 2 θ, about 13.7 ° 2 θ, about 17.4 ° 2 θ, about 18.1 ° 2 θ, about 18.7 ° 2 θ, about 19.6 ° 2 θ, about 20.6 ° 2 θ, about 21.1 ° 2 θ, about 21.4 ° 2 θ, about 22.8 ° 2 θ, about 23.2 ° 2 θ, and about 23.7 ° 2 θ to characterize the 1: 1 eutectic crystal.

An XRPD pattern substantially the same as figure 1 and/or a DSC thermogram substantially the same as figure 4 may be used to characterize a co-crystal of fasorracetam and PABA, e.g., an R-fasorracetam and PABA co-crystal.

The R-fasoracetam PABA co-crystal process may be scaled up to provide grams or greater amount of R-fasoracetam PABA co-crystal. For example, a mixture of form I, form II, and anhydrous R-fasoracetam may be dissolved in a solvent, and a seed crystal of a co-crystal of PABA and R-fasoracetam PABA may be added to the solution. Separating the resulting solid to provide a co-crystal of R-fasorasitan and PABA. Alternatively, different forms of R-fasorasitan may be used, for example, form I R-fasorasitan monohydrate may be used as the starting material. Examples 6 and 7 provide such scaled-up examples. FIG. 23 is a representation of a peptide derived from 1: 1R-fasoracetam: a superposition of simulated XRPD patterns of single crystal x-ray solutions of the PABA co-crystal and XRPD patterns of the co-crystal made in example 6 shows a match. Fig. 25 also shows that the simulated diagram matches the diagram of example 7.

In other embodiments, the present disclosure provides crystalline fasoracetam urea, e.g., a co-crystal of fasoracetam and urea. In particular, the fasorasiracetam may be R-fasorasiracetam. As described herein, the co-crystal of R-fasorasiracetam and urea can be polymorphic (referred to herein as forms a and B). The crystal structure of form B shows that the crystal structure is 1: 1 eutectic crystal. Although there is no single crystal structure solution of form a herein, it is believed, without being bound by theory, that form a is a polymorph of form B (because both forms have the same stoichiometry) because, for example, the equimolar milling experiment (example 15) used to prepare form a does not show any residual XRPD signal associated with the starting material, as shown in figure 44, which is an XRPD pattern corresponding to a co-crystal of form a of R-fasoracetam and urea. To prepare the co-crystals, following the general method of example 11 and/or example 16, a mixture of R-fasoracetam forms was obtained. The mixture comprises R-fasoracetam in form I, form II and anhydrous form (R-fasoracetam form mixture), and figure 18 shows an XRPD pattern of the mixture, compared to a simulated plot of the components. The XRPD pattern of the mixture is a linear combination of pure simulated patterns (varying in intensity), confirming the presence of the mixture. For example, for the first 7 peaks of the mixture diffraction pattern, these peaks correspond to the peaks in one of the simulated patterns, respectively. The peaks at about 5.7 ° 2 θ and about 11.3 ° 2 θ correspond to form II. The peaks at about 7.2 ° 2 θ correspond to form I, and the peaks at about 8.9 ° 2 θ, about 12.3 ° 2 θ and about 13.1 ° 2 θ correspond to anhydrate. The peak at about 12.9 ° 2 θ corresponds to form I, but also approaches 13.1 ° 2 θ in the anhydrate. However, form I and anhydrate explain these two peaks between about 12.8 ° 2 θ and about 13.2 ° 2 θ. It is also noteworthy that at angles below about 14 ° 2 θ, the overall intensity of the type I peak is much weaker than the type II and anhydrous forms. Simulated XRPD patterns can be found in fig. 33 (R-fasoracetam type I), 28 (R-fasoracetam type II), and 30 (anhydrous R-fasoracetam).

FIG. 35 is a superposition of the XRPD pattern of the co-crystal of R-fasoracetam form A and urea of example 16 and the XRPD pattern of urea (FIGS. 45 and 113) and the XRPD pattern of the mixture of R-fasoracetam forms. The XRPD pattern of urea in fig. 45 is shifted by about 0.3 ° 2 θ relative to the urea XRPD pattern of fig. 113. The offset in figure 45 is due to experimental error caused by the sample holder during XRPD measurements. The XRPD pattern of figure 113 is a more accurate XRPD pattern with no such sample holder errors occurring during its measurement. Figure 124 is a simulated XRPD pattern of urea. Some peaks in the experimental diffractogram of urea (fig. 113), for example peaks at about 24.5 ° 2 θ, are not visible due to the preferred orientation of the urea crystals.

The XRPD pattern of the co-crystal form a has a unique pattern that cannot be described as a linear combination of the XRPD patterns of a mixture of urea and R-fasoracetam forms. For example, the peak at about 10.4 ° 2 θ is neither in urea nor in the R-fasorasitan form mixture. Also, since there are no peaks at about 5.7 ° 2 θ and about 8.9 ° 2 θ, there is no evidence of form II or anhydrous form in this eutectic XRPD pattern. The XRPD pattern of form I shows peaks at about 7.2 ° 2 θ and 12.9 ° 2 θ, both of which are absent from the XRPD pattern of the co-crystal form a of R-fasoracetam and urea. Thus, the XRPD pattern of fig. 44 of the milled crystalline material of example 15 does not represent a mixture of urea and R-fasorasitan, but rather a new crystalline phase. It is a type a co-crystal of R-fasorasitan and urea, and the peak at about 10.4 ° 2 θ is a characteristic peak that is characteristic of a co-crystal of R-fasorasitan and urea, although this peak is susceptible to preferred orientation effects and is not visible in all experimental figures, such as in figures 115 and 117. This peak is also present in the co-crystal of R-fasorasitan and urea type B, and therefore, although this peak alone cannot distinguish between type a and type B, it does distinguish from the starting material and is therefore characteristic of a co-crystal of R-fasorasitan and urea (e.g. a co-crystal of type a or type B). Another common peak is a peak at about 14.0 ° 2 θ or about 14.1 ° 2 θ. The peak at about 14.0 ° 2 θ appears in form B, and the peak at about 14.1 ° 2 θ appears in form a. The difference at 0.1 ° 2 θ is within the typical variability of XRPD peaks. Thus, like the peak at about 10.4 ° 2 θ, the peak at about 14.0 ° 2 θ or at about 14.1 ° 2 θ can be used to characterize a co-crystal of R-fasorracetam and urea, e.g., form a or form B or both. Additionally, one or more XRPD peaks selected from about 10.4 ° 2 θ, about 10.8 ° 2 θ, about 12.2 ° 2 θ, about 14.1 ° 2 θ, about 16.1 ° 2 θ, about 18.9 ° 2 θ, about 22.3 ° 2 θ, and about 22.9 ° 2 θ can be used to characterize the R-fasoracetam type a co-crystal with urea. With respect to the distinction between form a and form B, a peak at about 16.1 ° 2 θ can distinguish form a from form B because there is no corresponding peak in form B. Likewise, a peak at about 12.2 ° 2 θ can distinguish form a from form B. Thus, for example, a peak at about 12.2 ° 2 θ or a peak at about 16.1 ° 2 θ, or both, and one or more peaks selected from about 10.4 ° 2 θ, about 10.8 ° 2 θ, about 14.1 ° 2 θ, about 18.9 ° 2 θ, about 22.3 ° 2 θ, and about 22.9 ° 2 θ may be used to characterize form a. FIGS. 114 and 115 illustrate the differences in XRPD patterns between form A, form B, urea, R-fasoracetam form mixture, anhydrate, form I and form II.

The melting properties can also be used to characterize a co-crystal of fasorasitan and urea, such as a co-crystal of R-fasorasitan and urea. For example, a sample that is considered to be a type A co-crystal of R-fasorracetam and urea when measured using differential scanning calorimetry has an onset of melting point of about 103 deg.C, as shown in FIG. 47, a DSC onset melting temperature that is well below about 133 deg.C for urea, and is well above the DSC onset melting point temperature of form I (about 52 deg.C as shown in FIG. 8; about 57 deg.C as shown in FIG. 9), form II (about 93 deg.C as shown in FIG. 17), or the anhydrous form of R-fasorracetam (about 93 deg.C as shown in FIG. 20, about 94 deg.C as shown in FIG. 21, where the rate of temperature change increases to about 10 deg.C/minute). (Anhydrous matter is hygroscopic, and the sample in FIG. 21 was obtained by keeping form I R-fasoracetam monohydrate at a temperature of 65 ℃ under vacuum for a long time to limit water absorption.)

However, the 103 ℃ DSC measurement in figure 47 actually corresponds to form B, since it was determined that form B is thermodynamically more stable R-fasorasitan than form a: urea eutectic form, type a material is converted to type B before or during DSC measurement. A more representative DSC of form A can be found in FIG. 119, which has an initial melting point of about 91 ℃. Such co-crystals may also be characterized by a combination of the melting onset temperature (e.g. when measured by DSC) and one or more characteristic XRPD peaks. Thus, for example, an initial melting temperature of about 91 ℃ can be used with one or more peaks selected from peaks at 10.4 ° 2 θ, about 10.8 ° 2 θ, about 12.2 ° 2 θ, about 14.1 ° 2 θ, about 16.1 ° 2 θ, about 18.9 ° 2 θ, about 22.3 ° 2 θ, or about 22.9 ° 2 θ to characterize a co-crystal of fasorafeptan and urea, e.g., a co-crystal of R-fasorasitan and urea type a.

An XRPD pattern substantially the same as figure 44 and/or a DSC thermogram substantially the same as figure 119 can be used to characterize the R-fasorracetam and urea type a co-crystal.

In various embodiments, the present disclosure provides a co-crystal of R-fasoracetam and urea type B. The ORTEP plot of the co-crystal is shown in fig. 36, which is from the single crystal solution of form B in example 12. As shown in figure 127, R-fasorexiptan (left, two molecules on top of each other, right) and urea (two central molecules) were mixed at 1: 1 by crystallization.

Without being bound by theory, it is believed that R-FasorasiCarbonyl groups on the five-membered ring of the amine act as hydrogen donors NH for urea₂The carbonyl group of urea acts as an acceptor for the NH hydrogen donor on the five-membered ring of R-fasoracetam. It is generally believed that the NH donor from the hydrogen on urea₂Another hydrogen bond with the bridging carbonyl on R-fasorasitan serves to join different layers of the molecule together, forming a 3D hydrogen bond diagram.

The simulated pattern of the single crystal solution in fig. 37 does not match when compared with the X-ray powder diffraction pattern of form a in fig. 49, and there are many peaks in form B that are not in form a. For example, the peak at about 11.4 ° 2 θ in form B is not in form a, and thus the peak can be used to distinguish and characterize form B. Likewise, there is no peak at about 17.5 ° 2 θ in form a, so it can also be used to distinguish and characterize form B from form a. Form B also has three peaks between about 14.0 ° 2 θ and about 14.9 ° 2 θ, namely about 14.0 ° 2 θ, about 14.5 ° 2 θ and about 14.9 ° 2 θ. In contrast, form a has a peak at about 14.1 ° 2 θ. Thus, the presence of two of the three peaks at about 14.0 ° 2 θ, about 14.5 ° 2 θ, and about 14.9 ° 2 θ can characterize form B, such as the peaks at about 14.5 ° 2 θ and about 14.9 ° 2 θ. In other embodiments, a peak at about 14.9 ° 2 θ may characterize form B.

In other embodiments, the co-crystal of form B of R-fasorasiracetam and urea can be characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from peaks at about 11.4 ° 2 Θ, about 14.0 ° 2 Θ, about 14.5 ° 2 Θ, about 14.9 ° 2 Θ, and about 17.5 ° 2 Θ. Other embodiments may also be used to characterize form B. For example, form B can also be characterized by: a peak at about 11.4 ° 2 θ, and one or more peaks selected from peaks at about 10.4 ° 2 θ, about 14.0 ° 2 θ, about 14.5 ° 2 θ, about 14.9 ° 2 θ, about 17.5 ° 2 θ, about 18.4 ° 2 θ, about 18.7 ° 2 θ, about 19.4 ° 2 θ, about 20.1 ° 2 θ, and about 21.1 ° 2 θ. In addition, an XRPD diffractogram substantially the same as that of fig. 37 may be used to characterize form B.

Form B can also be characterized by an initial melting point of 102 ℃. Melting points, such as those measured by DSC, may also be combined with the x-ray powder diffraction embodiments of form B herein to characterize form B and distinguish form B from form a.

Type B co-crystals of R-fasoracetam and urea were also prepared by liquid assisted milling as described in example 13, using an R-fasoracetam form mixture and urea as starting materials. Figure 38 shows the x-ray powder diffraction pattern obtained from example 13 superimposed with the simulated x-ray powder diffraction pattern of the single crystal from example 12. The peaks of the two figures match, but there are some additional peaks in the example 13 figure that are not present in the simulated figure. FIG. 39 is a superimposed plot of the constituents of a mixture of R-fasorasitan forms, showing that these additional peaks may be due to the presence of unreacted starting materials in the preparation of example 13, such as form I, form II, and R-fasorasitan monohydrate, as well as the anhydrate. FIG. 40 is a DSC thermogram of form B showing a melting temperature of about 102 ℃.

Form B was also prepared by the rotary evaporation experiment in example 14. There, the starting materials are R-fasorasitan form I and urea. In the melting-recrystallization experiment, a eutectic of R-fasoracetam form B and urea was formed, and as shown in fig. 41, fig. 41 is a superimposed graph of the diffraction pattern obtained in example 14 and the simulated X-ray powder diffraction pattern of example 12. As with the liquid-assisted milling experiment of example 13, the experimental co-crystal matched the simulated pattern, but also contained some R-fasoracetam monohydrate and anhydrate impurities. Here, the impurity appears to be predominantly type II, but some type I may also be present, as shown in the superimposed diagram in fig. 42.

The specifically measured initial melting points of the form I, form II, anhydrate, urea, and form a and B fasoracetam co-crystals are listed in table 3B below. The table illustrates the general difference in melting point between the various materials.

TABLE 3 onset melting temperatures of form B-R-fasorasitan, Urea, form A and B

Crystal form	Melting Start temperature (. degree.C.)
		I type R-fasoracetam monohydrate	About 57 deg.C
II type R-fasoracetam monohydrate	About 49 deg.C
		Anhydrous R-fasorasitan	About 94 deg.C
Urea	About 133 deg.C
		Type a R-fasorasitan: urea eutectic	About 91 deg.C
Type B R-fasoracetam: urea eutectic	About 102 deg.C

The initial attempts to prepare a co-crystal of fasorracetam and urea resulted in form a, while further attempts resulted in form B. In fact, when form B is present, form a is converted to form B in both the suspended state and the solid state, and attempts to prepare form a from form B have failed. Figure 122 shows the solid state conversion of form a to form B over time upon exposure to air at room temperature for three days. Also, as shown in FIG. 123, this conversion also occurred in a closed container at-15 ℃ when the samples were measured daily.

Various processes can be used to make form B. For example, form B can be prepared by milling, from a melt or from solution-based chemistry. Solution-based methods may be particularly suitable for scale-up, while melting regimes are suitable for growing single crystals of type B.

In a solution state process, one can generally start with a solution of R-fasorasitan (as starting material) in a suitable solvent to which urea is added. The R-fasorasitan may be dissolved using a suitable solvent. The temperature is controlled to promote crystallization and seeds of previously prepared type B co-crystals may be added (and by the same or other methods). Various parameters may be controlled to improve the quality and yield of the resulting type B co-crystal. Such parameters include the identity and amount of the appropriate solvent, the identity and amount of the R-fasoracetam feedstock, the amount of urea added, the presence of seed crystals, and the temperature profile of the process used to prepare form B.

A typical starting material is R-fasorasiracetam form I, although other starting materials for fasorasiracetam, such as form mixtures, form II, amorphous form or anhydrous form, can also be used as starting materials. When the starting material is form I R-fasorasiracetam, in many embodiments, the ratio of suitable solvent to form I R-fasorasiracetam is from about 2.5ml of suitable solvent to about 6ml of suitable solvent per gram of form I R-fasorasiracetam used. Other ranges include about 3.0ml to 5.0ml and about 3.8ml to about 4.6ml of a suitable solvent. Examples of suitable solvents include isopropyl acetate, ethyl acetate, and mixtures thereof. The solvent range includes the solvent initially added to R-fasorasiracetam, as well as any rinse that may be used when combining aliquots, such as seen in example 42.

When the R-fasorasitan feedstock is combined with a solvent, the temperature of the composition can be adjusted to be below, at, or above room temperature. Examples of temperature ranges include about 10 ℃ to 15 ℃, about 15 ℃ to 20 ℃, about 20 ℃ to 25 ℃, about 25 ℃ to 30 ℃, about 30 ℃ to 35 ℃, about 35 ℃ to 40 ℃, about 40 ℃ to 45 ℃, about 45 ℃ to 50 ℃, about 50 ℃ to 55 ℃, about 55 ℃ to 60 ℃, about 60 ℃ to 65 ℃, or about 65 ℃ to 70 ℃.

Once the R-fasorasitan and suitable solvent combination is prepared, the urea can be added in portions or all at once. The amount of urea added is related to the amount of R-fasorasitan feedstock present. Typically, urea is used in an amount of about 0.70 to about 1.2 equivalents on a molar basis relative to the fasorasitan feedstock. Specific equivalents include about 0.70, about 0.71, about 0.72, about 0.73, about 0.74, about 0.75, about 0.76, about 0.77, about 0.78, about 0.79, about 0.80, about 0.81, about 0.82, about 0.83, about 0.84, about 0.85, about 0.86, about 0.87, about 0.88, about 0.89, about 0.90, about 0.91, about 0.92, about 0.93, about 0.94, about 0.95, about 0.96, about 0.97, about 0.98, about 0.99, about 1.0, about 1.1, or about 1.2, or any range within, for example, about 0.95 to 1.0. Pre-prepared type B R-fasorasitan: seed crystals of the urea co-crystal (e.g. by grinding or other methods) may be added with or after the urea. After addition is complete, the composition is typically cooled and then washed to provide R-fasorasitan form B: the urea co-crystal may also be dried.

In further embodiments, the present disclosure provides crystals of fasoracetam trimesic acid, e.g., a co-crystal of fasoracetam and trimesic acid. In particular, the fasorasiracetam may be R-fasorasiracetam. FIG. 51 is an X-ray powder diffraction pattern corresponding to a cocrystal of R-fasoracetam and trimesic acid. The co-crystal was prepared according to example 17. The co-crystal was prepared by milling form I with trimesic acid. Figure 50 is an overlay of XRPD patterns showing trimesic acid, form I, and co-crystals. Fig. 50 shows that the eutectic pattern is not a linear combination of the constituent parts and therefore is not a physical mixture. For example, no peak at about 9.7 ° 2 θ in the co-crystal is present in the XRPD pattern of the constituent parts. Thus, the XRPD pattern of FIG. 51 of example 17 does not represent a mixture of trimesic acid and R-fasoracetam, but rather a new crystalline phase. It is a co-crystal of R-Larasitan and trimesic acid.

The co-crystal of valsartan and trimesic acid (e.g., R-valracetam and trimesic acid) can be characterized by a peak at about 9.7 ° 2 θ. In addition, one or more peaks selected from peaks at about 10.9 ° 2 θ, about 11.4 ° 2 θ, about 14.6 ° 2 θ, about 16.5 ° 2 θ, about 17.5 ° 2 θ, about 18.6 ° 2 θ, about 19.4 ° 2 θ, about 19.8 ° 2 θ, about 21.8 ° 2 θ, about 23.5 ° 2 θ, about 26.7 ° 2 θ, and about 27.3 ° 2 θ may be used with or without a peak at about 9.7 ° 2 θ to characterize such a co-crystal. In addition, an initial melting point of about 96 ℃ (e.g., melting point measured by DSC) may be used to characterize such a co-crystal. This melting point can be used alone or in combination with the XRPD peaks to characterize the co-crystal. That is, an initial melting point of about 96 ℃ (as shown in fig. 54) may be used with one or more peaks selected from peaks at about 9.7 ° 2 θ, 10.9 ° 2 θ, about 11.4 ° 2 θ, about 14.6 ° 2 θ, about 16.5 ° 2 θ, about 17.5 ° 2 θ, about 18.6 ° 2 θ, about 19.4 ° 2 θ, about 19.8 ° 2 θ, about 21.8 ° 2 θ, about 23.5 ° 2 θ, about 26.7 ° 2 θ, and about 27.3 ° 2 θ to characterize such a eutectic.

An XRPD pattern substantially the same as figure 51 and/or a DSC thermogram substantially the same as figure 54 can be used to characterize the R-fasoracetam and trimesic acid co-crystal.

Other embodiments of the disclosure relate to co-crystals of R-fasorasitan and R-ibuprofen. In example 18, a 1: 1 single crystal of a co-crystal of R-fasoracetam and R-ibuprofen was prepared and the structure was resolved. An ORTEP chart illustrating this solution is set forth in fig. 56, with the single data parameter in table 8 representing 1: 1 in stoichiometric ratio. In fig. 134, co-crystals of R-fasorasiracetam and (R) -ibuprofen are shown in a hydrogen bond diagram. It can be seen that an acid-amide hetero synthon exists between R-fasorasitan and ibuprofen.

Without being bound by theory, it is believed that the NH on the five-membered ring of R-fasoracetam acts as a hydrogen donor, wherein the carbonyl group of the carboxylic acid on ibuprofen acts as a hydrogen acceptor, and the hydroxyl moiety of the carboxylic acid of ibuprofen acts as a hydrogen donor, the carbonyl group on the five-membered ring facing away from R-fasoracetam forming a hydrogen bond.

Based on the single crystal solution, a simulated XRPD pattern of the single crystal is given in fig. 57. Figure 59 is an XRPD pattern of R-ibuprofen. Based on single crystal simulated XRPD patterns, multiple peaks can be used to characterize co-crystals of R-fasoracetam and R-ibuprofen. For example, any one or more peaks selected from peaks at about 5.6 ° 2 θ, about 10.5 ° 2 θ, about 11.2 ° 2 θ, about 12.3 ° 2 θ, about 17.4 ° 2 θ, about 20.1 ° 2 θ, and about 20.6 ° 2 θ may be used to characterize such a eutectic.

A milled crystalline material of R-ibuprofen and R-fasoracetam was prepared as in example 19, with the XRPD pattern shown in figure 58. XRPD patterns of the component compound I, R-fasoracetam monohydrate and R-ibuprofen are respectively shown in figure 7 and figure 59. A comparison between figure 58 and figures 7 and 59 shows that the milled crystalline material is not a mixture of R-ibuprofen and R-fasoracetam monohydrate form I. For example, the milled crystalline material has peaks at about 5.5 ° 2 θ and about 10.9 ° 2 θ in the XRPD pattern, which is not present in the XRPD pattern of either component compound. Thus, the milled crystalline material of R-fasorasitan and R-ibuprofen is a new crystalline phase. It is a eutectic crystal of R-fasoracetam and R-ibuprofen. When comparing the XRPD pattern of the milled co-crystal of example 19 with the simulated XRPD pattern of the single crystal X-ray solution taken from example 18, there is some difference in the peaks, for example where the peaks at about 20.1 ° 2 θ and about 20.6 ° 2 θ are shifted by 0.3 °. Thus, for example, the co-crystal of example 19 may be the same co-crystal as example 18 or a polymorph or hydrate thereof. R-fasorasiracetam of example 19: the melting onset temperature of the R-ibuprofen co-crystal is about 115 ℃, which is about 63 ℃ higher than the melting point of form I R-fasoracetam monohydrate, and about 63 ℃ higher than the melting temperature of the R-ibuprofen.

Other embodiments of the present disclosure relate to crystalline fasoracetam phthalic acid, e.g., a co-crystal of fasoracetam and phthalic acid. In particular, the fasorasiracetam may be R-fasorasiracetam. In example 20, a co-crystal of R-fasoracetam phthalic acid was prepared and the single crystal X-ray solution was analyzed using the data sheet for the parameters listed in table 9 and the ORTEP plot in figure 63 (indicating 1: 1 stoichiometry). FIG. 128 depicts, in a hydrogen bond diagram, phthalic acid (central 4 molecules) and R-fasorasiracetam (peripheral molecules, two on the left, one on the right) in a 1: 1 manner.

Without being bound by theory, it is believed that one intramolecular hydrogen bond exists between two carboxylic acids adjacent to each other of the phthalic acid, and the other hydrogen bond is between the carboxylic acid of the phthalic acid (donor) and the carbonyl moiety on the five-membered ring of R-fasoracetam (acceptor). It is also believed that the two carboxylic acid moieties of phthalic acid form a ribbon-like (ribbon-like) hydrogen bonding network, where each carboxylic acid moiety forms a hydrogen bond with the R-fasoracetam molecule. The simulated XRPD pattern is shown in fig. 64, and the experimental XRPD pattern of the starting material is shown in fig. 7 (for form I) and fig. 65 (for phthalic acid). Based on single crystal simulated XRPD patterns, various peaks can be used to characterize the co-crystal of R-fasoracetam phthalic acid. For example, any one or more peaks selected from peaks at about 6.1 ° 2 θ, about 12.4 ° 2 θ, about 15.1 ° 2 θ, about 15.8 ° 2 θ, about 18.1 ° 2 θ, about 19.9 ° 2 θ, and about 23.3 ° 2 θ may be used to characterize such a eutectic.

Other embodiments of the present disclosure relate to crystalline fasoracetam phloroglucinol, e.g., a co-crystal of fasoracetam and phloroglucinol. In particular, the fasorasiracetam may be R-fasorasiracetam. In example 22, a co-crystal of R-fasoracetam phloroglucinol was prepared and the single crystal X-ray solution was analyzed using the data sheet for the parameters listed in Table 10 and the ORTEP chart in FIG. 71 (indicating a 1: 1 stoichiometric ratio of R-fasoracetam: phloroglucinol: water, making the co-crystal a monohydrate). In fig. 129, phloroglucinol (middle, top) and R-fasorasitan (left, right) form a eutectic monohydrate in a hydrogen bonding mode.

Without being bound by theory, it is believed that two of the three carboxylic acids on phloroglucinol act as hydrogen donors, with the bridging atoms and the carbonyl groups on the five-membered ring of R-fasoracetam acting as hydrogen acceptors. Furthermore, it is believed that water acts as a hydrogen donor for the carboxylic acid of phloroglucinol, linking water to another phloroglucinol molecule, in this alternating manner to form a chain (not shown). It is also believed that the last hydrogen bond is from the-NH moiety on the five-membered ring of R-fasoracetam, which acts as a hydrogen donor, and the carbonyl group acts as a hydrogen acceptor on the five-membered ring of another R-fasoracetam molecule.

The simulated XRPD pattern is shown in fig. 72, and the experimental pattern of the starting material is shown in fig. 7 (for form I) and fig. 67 (for phloroglucinol). Based on single crystal simulated XRPD patterns, various peaks can be used to characterize co-crystals of R-fasoracetam and phloroglucinol. For example, any one or more peaks selected from peaks at about 6.9 ° 2 θ, about 10.3 ° 2 θ, about 15.3 ° 2 θ, about 16.2 ° 2 θ, about 17.3 ° 2 θ, about 21.6 ° 2 θ, about 22.6 ° 2 θ, and about 25.3 ° 2 θ may be used to characterize such a eutectic. The monohydrate co-crystal of R-fasorasitan and phloroglucinol was further characterized in example 21 by milling R-fasorasitan form I and phloroglucinol. The resulting XRPD matched the simulated pattern, as shown in fig. 73.

Other embodiments of the present disclosure relate to crystalline fasoracetam methyl-3, 4, 5-trihydroxybenzoate, e.g., a co-crystal of fasoracetam and methyl-3, 4, 5-trihydroxybenzoate. In particular, the fasorasiracetam may be R-fasorasiracetam. In example 23, a co-crystal of R-fasoracetam and methyl-3, 4, 5-trihydroxybenzoate was prepared and the single crystal X-ray solution was analyzed using the data sheet for the parameters listed in Table 11 and the ORTEP chart in FIG. 74 (indicating that R-fasoracetam: methyl-3, 4, 5-trihydroxybenzoate: water is 1: 1 stoichiometrically, making the co-crystal a monohydrate). The R-fasoracetam (left), methyl-3, 4, 5-trihydroxybenzoate (right) is shown in figure 130 as a hydrogen bonding network.

Without being bound by theory, it is believed that there are two direct hydrogen bonds between the two different compounds, one from the hydroxyl group at the 4-position of the phenyl ring of methyl-3, 4, 5-trihydroxybenzoate, supplying hydrogen to the five-membered ring (carbonyl) of R-fasoracetam, and supplying hydrogen from the nitrogen atom of the five-membered ring of R-fasoracetam to the hydroxyl group at the 3-position of the phenyl ring of methyl-3, 4, 5-trihydroxybenzoate. It is believed that the hydrogen bond between the bridging carbonyl (acceptor) of R-fasorasitan and the water molecule (donor) is back-bound to the methyl-3, 4, 5-trihydroxybenzoate, from the water molecule (hydrogen acceptor) to the hydroxyl group in three positions of the phenyl ring (donor). It is also believed that the same water molecule also acts as a hydrogen donor in the third hydrogen bond, with the second R-fasoracetam molecule acting as a hydrogen acceptor through the carbonyl group on its five-membered ring.

The simulated XRPD patterns are shown in fig. 75, and the experimental patterns of the starting material are shown in fig. 7 (for form I) and fig. 77 (for methyl-3, 4, 5-trihydroxybenzoate). Based on single crystal simulated XRPD patterns, various peaks can be used to characterize co-crystals of R-fasorasitan and methyl-3, 4, 5-trihydroxybenzoate. For example, any one or more peaks selected from peaks at about 5.7 ° 2 θ, about 10.6 ° 2 θ, about 11.3 ° 2 θ, about 12.7 ° 2 θ, about 16.6 ° 2 θ, about 18.9 ° 2 θ, about 20.6 ° 2 θ, about 24.3 ° 2 θ, and about 25.0 ° 2 θ may be used to characterize such a eutectic.

In other embodiments of the present disclosure, crystalline fasoracetam ethyl gallate is provided, for example, a co-crystal of fasoracetam and ethyl gallate. In particular, the fasorasiracetam may be R-fasorasiracetam. In certain of these embodiments, there is provided a 1: 1 eutectic crystal. In example 24, a co-crystal of R-fasoracetam and ethyl gallate was prepared and the single crystal X-ray solution was analyzed using the data table for the parameters listed in Table 12 and the ORTEP plot in FIG. 78 (indicating a 1: 1 stoichiometry for R-fasoracetam: ethyl gallate). Fig. 131 shows 1: 1R-fasorasitan: asymmetric units of ethyl gallate eutectic and hydrogen bond patterns thereof, wherein R-fasoracetam molecules are positioned at the upper left and the center, and ethyl gallate molecules are positioned at the lower left and the right.

Without being bound by theory, it is believed that there are five unique intermolecular hydrogen bonds. The carbonyl group on the five-membered ring of R-fasoracetam acts as a hydrogen acceptor for the hydrogen donor of the 3-hydroxyl group of ethyl gallate. The same carbonyl group is also an acceptor for hydrogen bonding from the hydroxyl group at the 4-position of ethyl gallate. However, it appears that this hydrogen bond is shared with the hydrogen accepting carbonyl group on the bridging carbon atom of R-fasorasiracetam. The hydrogen donor on the NH of the five-membered ring of R-fasoracetam forms a hydrogen bond with the oxygen atom of the hydroxyl group at position 4 of ethyl gallate (acting as an acceptor). Finally, the-NH in the five-membered ring of another R-fasoracetam molecule acts as a hydrogen donor, linking it to the original R-fasoracetam molecule through a bridging carbonyl (acting as a hydrogen acceptor).

The simulated XRPD patterns are shown in fig. 79, and the experimental patterns of the starting material are shown in fig. 7 (for form I) and fig. 82 (for ethyl gallate). Based on single crystal simulated XRPD patterns, various peaks can be used to characterize the co-crystal of R-fasoracetam ethyl gallate. For example, any one or more peaks selected from peaks at about 5.8 ° 2 θ, about 11.3 ° 2 θ, about 12.4 ° 2 θ, about 15.5 ° 2 θ, about 15.8 ° 2 θ, about 18.2 ° 2 θ, about 19.4 ° 2 θ, about 22.0 ° 2 θ, or about 24.8 ° 2 θ may be used to characterize such a eutectic. The co-crystal of R-fasoracetam and ethyl gallate was further characterized by milling type I R-fasoracetam and ethyl gallate in example 25. The resulting XRPD matches the simulated pattern shown in figure 81.

For 1 of example 25: the 1R-fasoracetam co-crystal with ethyl gallate, as shown in fig. 83, measured an initial melting point temperature of about 112 ℃. An initial melting point of 112 ℃ can be used to characterize this co-crystal of R-fasoracetam and ethyl gallate. In other embodiments, both DSC onset melting temperature and XRPD peaks may be used to characterize such co-crystals of R-fasorasitan and ethyl gallate. Thus, a DSC melting point onset temperature of about 112 ℃ may be used with one or more peaks selected from 5.8 ° 2 θ, about 11.3 ° 2 θ, about 12.4 ° 2 θ, about 15.5 ° 2 θ, about 15.8 ° 2 θ, about 18.2 ° 2 θ, about 19.4 ° 2 θ, about 22.0 ° 2 θ, and about 24.8 ° to characterize such a eutectic. In addition, the XRPD pattern in fig. 79 and/or the DSC thermogram in fig. 83 can be used to characterize the 1: 1 eutectic crystal.

In other embodiments, there is provided a 1: 2 eutectic crystal. In example 27, a co-crystal of R-fasorasitan ethyl gallate was prepared and the single crystal X-ray solution was analyzed using the data sheet for the parameters listed in Table 13 and the ORTEP plot in FIG. 85 (indicating 1: 2 stoichiometry for R-fasorasitan: ethyl gallate). Figure 132 shows a hydrogen bonding diagram of a second co-crystal of R-fasorasiracetam (top right, center) with ethyl gallate (bottom two left, two lying flat into the paper).

Without being bound by theory, it is believed that all three hydroxyl groups of the ethyl gallate act as hydrogen donors and acceptors, with the hydroxyl groups at the 3 and 5 positions forming hydrogen bonds with the hydroxyl group at the 4 position on the adjacent ethyl gallate molecule (which lies flat and points to the plane). It is also believed that the hydroxyl group at the 4-position on both molecules of ethyl gallate also forms hydrogen bonds with the-NH and the carbonyl group on the five-membered ring of R-fasoracetam, which is strictly a hydrogen acceptor, but that-NH is both a hydrogen donor and acceptor. The reason for this is believed to be that each hydroxyl group participates in two different intermolecular hydrogen bonds due to the degree of linkage of the 3D hydrogen bond diagram. The ethyl ester of ethyl gallate points away from the interaction site.

The simulated XRPD patterns are shown in fig. 86, and the experimental patterns of the starting material are shown in fig. 7 (for form I) and fig. 82 (for ethyl gallate). Based on single crystal simulated XRPD patterns, various peaks can be used to characterize the co-crystal of R-fasoracetam and ethyl gallate. For example, any one or more peaks selected from peaks at about 5.8 ° 2 θ, about 7.2 ° 2 θ, about 14.8 ° 2 θ, about 20.4 ° 2 θ, about 21.9 ° 2 θ, or about 23.5 ° 2 θ can be used to characterize such 1: 2 eutectic crystal.

In other embodiments of the present disclosure, the ratio of 1: 1: 2 stoichiometrically provides R-fasorasitan: and 4, ethyl gallate: and (4) water eutectic crystal. Suitable for this 1: 2R-fasoracetam and ethyl gallate dihydrate. The single crystal X-ray solutions were analyzed using the data tables for the parameters listed in table 14 and the ORTEP plot in fig. 87 (indicating 1: 1: 2 stoichiometry of R-fasoracetam: ethyl gallate: water). The hydrogen bonding diagram for the third co-crystal of R-fasorasitan and ethyl gallate (1: 2: 2 co-crystal dihydrate) is shown in fig. 133, with the left side view showing in-plane hydrogen bonding.

Without being bound by theory, it is believed that the ethyl gallate on the left acts as a hydrogen acceptor, where the donor is-NH on the five-membered ring of R-fasoracetam. In the side view, the bridged carbonyl group of R-fasorasitan acts as a hydrogen acceptor, and the-NH in the five-membered ring of the right R-fasorasitan acts as a hydrogen donor. In the plane itself (top view), the 2D hydrogen bond network consists of two molecules of ethyl gallate, two molecules of water, and one molecule of R-fasoracetam. It is believed that the water molecules act as bridges between the larger molecules, at the bottom between the hydroxyl group at the 3-position of the ethyl gallate (left) and the carbonyl group of the ester of another ethyl gallate molecule (right).

It is also believed that the hydroxyl groups at both the 4 and 5 positions of the same ethyl gallate molecule on the left act as hydrogen donors, forming hydrogen bonds with the ethyl gallate on the right (the hydroxyl group at the 3 position acts as a hydrogen acceptor) and the R-fasoracetam on the upper left, where the carbonyl on the five-membered ring acts as a hydrogen acceptor. It is believed that this same carbonyl group also serves as an acceptor for the hydrogen donor for water, which in turn serves as a hydrogen acceptor for the 3-hydroxyl hydrogen donor of ethyl gallate (lower right) and the 4-hydroxyl hydrogen donor of the upper right ethyl gallate. It is also believed that the 3-position of the hydroxyl group of the upper right gallic acid ethyl ester acts as a hydrogen donor, with the bridging carbonyl group on R-fasorasitan being the hydrogen acceptor.

The simulated XRPD pattern is shown in fig. 88, and the experimental XRPD pattern of the starting material is shown in fig. 7 (for form I) and in fig. 82 (for ethyl gallate). Based on single crystal simulated XRPD patterns, various peaks can be used to characterize the co-crystal of R-fasoracetam ethyl gallate. For example, any one or more peaks selected from peaks at about 8.8 ° 2 θ, about 11.2 ° 2 θ, about 19.4 ° 2 θ, about 19.9 ° 2 θ, or about 24.1 ° 2 θ may be used to characterize such a eutectic. The co-crystal of R-fasorasitan and ethyl gallate was further characterized by slurrying form I R-fasorasitan and 2 equivalents of ethyl gallate in water, as described in example 29. The resulting XRPD pattern matches the simulated pattern shown in figure 90.

In other embodiments, the present disclosure provides crystalline fasoracetam 6-hydroxy-2-naphthoic acid, e.g., a co-crystal of fasoracetam and 6-hydroxy-2-naphthoic acid. In particular, the fasorasiracetam may be R-fasorasiracetam. FIG. 93 is an XRPD pattern corresponding to a co-crystal of R-fasorasiracetam and 6-hydroxy-2-naphthoic acid. A co-crystal was prepared according to example 30. The co-crystal was prepared by milling form I with 6-hydroxy-2-naphthoic acid. FIG. 94 is an XRPD pattern for 6-hydroxy-2-naphthoic acid, and FIG. 95 is an overlay showing a graph of 6-hydroxy-2-naphthoic acid, R-fasoracetam monohydrate form I, and a co-crystal of R-fasoracetam with 6-hydroxy-2-naphthoic acid. Fig. 95 shows that the eutectic pattern is not a linear combination of the constituent parts and is therefore not a physical mixture. For example, no peak at about 11.2 ° 2 θ in the co-crystal is present in the XRPD pattern of the constituent parts.

A co-crystal of fasorasitan and 6-hydroxy-2-naphthoic acid (e.g., R-fasorasitan and 6-hydroxy-2-naphthoic acid) can be characterized by one or more peaks at about 11.2 ° 2 Θ, about 14.9 ° 2 Θ, about 15.7 ° 2 Θ, about 20.1 ° 2 Θ, about 21.1 ° 2 Θ, about 23.6 ° 2 Θ, about 24.1 ° 2 Θ, about 25.0 ° 2 Θ, and about 25.5 ° 2 Θ. In addition, an initial melting point of about 120 ℃ (e.g., melting point measured by DSC) may be used to characterize such a co-crystal. This melting point can be used alone or in combination with the XRPD peaks to characterize the co-crystal. That is, an initial melting point of about 120 ℃ (as shown in fig. 97) may be used with one or more peaks selected from peaks at about 11.2 ° 2 θ, about 14.9 ° 2 θ, about 15.7 ° 2 θ, about 20.1 ° 2 θ, about 21.1 ° 2 θ, about 23.6 ° 2 θ, about 24.1 ° 2 θ, about 25.0 ° 2 θ, and about 25.5 ° 2 θ to characterize such a eutectic.

An XRPD pattern substantially the same as figure 93 and/or a DSC thermogram substantially the same as figure 97 can be used to characterize a fasoracetam and 6-hydroxy-2-naphthoic acid co-crystal, e.g., an R-fasoracetam and 6-hydroxy-2-naphthoic acid co-crystal.

In other embodiments of the present disclosure, crystalline fasoracetam 4-nitrobenzoic acid is provided, for example, a co-crystal of fasoracetam and 4-nitrobenzoic acid. In particular, the fasorasiracetam may be R-fasorasiracetam. In certain of these embodiments, there is provided a 1: 2 eutectic crystal. In example 31, a co-crystal of R-fasoracetam 4-nitrobenzoic acid was prepared and the single crystal X-ray solution was analyzed using the data sheet for the parameters listed in Table 15 and the ORTEP chart in FIG. 99 (indicating a 1: 2 stoichiometry for R-fasoracetam: 4-nitrobenzoic acid). FIG. 126 shows 4-nitrobenzoic acid (left and right) and R-fasorasiracetam (center).

Without being bound by theory, it is believed that both carbonyl groups on R-fasoracetam act as hydrogen acceptors, the hydrogen donor is the carboxylic acid group of 4-nitrobenzoic acid, and the aromatic ring orientation of the 4-nitrobenzoic acid molecule is such that there is a stable pi-pi interaction. The different molecules appear in an alternating manner, forming a sheet.

The simulated XRPD pattern is shown in figure 100 and the experimental pattern of the starting material is shown in figure 7 (for form I) and in figure 102 (for 4-nitrobenzoic acid). Based on single crystal simulated XRPD patterns, various peaks can be used to characterize the co-crystal of R-fasoracetam 4-nitrobenzoic acid. For example, any one or more peaks selected from peaks at about 6.5 ° 2 θ, about 6.7 ° 2 θ, about 8.9 ° 2 θ, about 14.5 ° 2 θ, about 15.6 ° 2 θ, about 17.9 ° 2 θ, about 18.6 ° 2 θ, about 19.8 ° 2 θ, about 23.4 ° 2 θ, or about 26.4 ° 2 θ may be used to characterize such a eutectic. The co-crystal of R-fasoracetam and 4-nitrobenzoic acid was further characterized in example 32 by milling R-fasoracetam form I and 4-nitrobenzoic acid. The resulting XRPD pattern matches the simulated pattern as shown in the overlay in fig. 104.

In other embodiments, the present disclosure provides crystalline fasorasitan 2-indole-3-acetic acid, e.g., a co-crystal of fasorasitan and 2-indole-3-acetic acid. In particular, the fasorasiracetam may be R-fasorasiracetam. FIG. 107 is an XRPD pattern corresponding to a co-crystal of R-fasorasiracetam and 2-indole-3-acetic acid. A co-crystal was prepared according to example 33. The co-crystal was prepared by grinding form I together with 2-indole-3-acetic acid. FIG. 108 is an XRPD pattern for 2-indole-3-acetic acid and FIG. 109 is an overlay showing a pattern of 2-indole-3-acetic acid, form I R-fasorasitan monohydrate, and a co-crystal of R-fasorasitan and 2-indole-3-acetic acid. The overlay in fig. 109 shows that the eutectic is not a linear combination of the components and is therefore not a physical mixture. For example, no peak at about 11.8 ° 2 θ in the co-crystal is present in the XRPD pattern of the constituent parts.

The co-crystal of fasorasitan and 2-indole-3-acetic acid (e.g., R-fasorasitan and 2-indole-3-acetic acid) can be characterized by one or more peaks selected from peaks at about 5.3 ° 2 Θ, about 7.9 ° 2 Θ, about 10.7 ° 2 Θ, about 14.7 ° 2 Θ, about 15.8 ° 2 Θ, about 18.0 ° 2 Θ, about 21.9 ° 2 Θ, about 23.1 ° 2 Θ, and about 23.5 ° 2 Θ. In addition, an initial melting point of about 69 ℃ (e.g., melting point measured by DSC) may be used to characterize such a co-crystal. In addition, the co-crystal can be characterized by a combination of the onset of melting temperature and XRPD peaks. For example, a melt initiation temperature of about 69 ℃ may be used with one or more peaks selected from peaks at about 5.3 ° 2 θ, about 7.9 ° 2 θ, about 10.7 ° 2 θ, about 14.7 ° 2 θ, about 15.8 ° 2 θ, about 18.0 ° 2 θ, about 21.9 ° 2 θ, about 23.1 ° 2 θ, and about 23.5 ° 2 θ to characterize a co-crystal of R-fasorracetam and 2-indole-3-acetic acid. An XRPD pattern substantially the same as figure 107 and/or a DSC thermogram substantially the same as figure 111 can be used to characterize a co-crystal of fasorracetam and 2-indole-3-acetic acid (e.g., R-fasorracetam and 2-indole-3-acetic acid).

Experimental data for the valracetam co-crystal were from experiments performed with the R-enantiomer of valracetam. Thus, all co-crystals were prepared with R-fasoracetam, and R-fasoracetam is the enantiomer of fasoracetam present in each co-crystal. It is expected that the S-enantiomer will also form a co-crystal with each achiral co-crystal former, as will the R-enantiomer. It is expected that the S-enantiomer does not necessarily form a co-crystal with a chiral co-crystal former (e.g. R-ibuprofen). However, for achiral co-crystal formers, it is desirable that the S-fasoraferacetam co-crystal have structural and property characteristics similar to those of the R-enantiomer, such as melting point properties and solubility characteristics. The racemic fasoracetam is not necessarily identical. It may form a co-crystal with the same achiral co-crystal former, but any co-crystal so produced may have different structural and property characteristics than the R-fasoracetam co-crystal.

The present disclosure also relates to pharmaceutical compositions comprising a co-crystal or crystalline compound of fasoracetam as disclosed herein. Such pharmaceutical compositions comprise one or more pharmaceutically acceptable excipients and a co-crystal or crystalline material of the present disclosure. Such pharmaceutical compositions may be administered orally or formulated to be delivered in any effective conventional dosage unit form, including immediate, slow and timed release oral formulations, parenteral, topical, nasal, ocular, optical (opthalmic), sublingual, rectal, vaginal, and the like.

The disclosure also includes methods and uses for treating human diseases such as ADHD, 22q11.2 deficiency syndrome, anxiety, conduct disorder, Tourette's syndrome, and anorexia with an effective amount of a co-crystal of fasoracetam, a crystalline compound, and/or a pharmaceutical composition comprising the co-crystal and/or the crystalline compound of the disclosure. In some embodiments, a patient with ADHD, 22q11.2 deficiency syndrome, anxiety, conduct disorder, Tourette's syndrome, or anorexia has at least one Copy Number Variation (CNV) in a metabotropic glutamate receptor (mGluR) network gene (see, e.g., figures 1-3 of WO 2017/044491). In some embodiments, the mGluR network gene is selected from the group consisting of GRM5, GRM8, GRM7, GRM1, NEGR1, SGTB/NLN, USP24, CNTN4, CTNNA2, LARP7, MC4R, SNCA, CA 8.

The following items provide many embodiments, and are not limiting:

a co-crystal of item 1, fasoracetam, and a co-crystal former, wherein the co-crystal former is not tartaric acid.

Item 2, the co-crystal of item 1, whereinThe co-crystal former is an organic compound and comprises at least one compound selected from-NH₂、-NO₂Alkyl, or a moiety containing a carbonyl moiety.

Item 3, the co-crystal of item 1 or item 2, wherein the fasoracetam is R-fasoracetam.

Item 4, a crystalline compound comprising fasorasitan and a co-crystal former, wherein the co-crystal former is an aromatic compound.

Item 5, a crystalline compound comprising R-fasorasitan and a co-crystal former, wherein the co-crystal former is an aromatic compound.

Item 6, the crystalline compound of item 4 or item 5, wherein the crystalline compound is a co-crystal.

A co-crystal of item 7, fasoracetam, and a co-crystal former, wherein the co-crystal former is an aromatic compound.

A co-crystal of item 8, R-fasorasitan, and a co-crystal former, wherein the co-crystal former is an aromatic compound.

Item 9, the co-crystal of item 7 or item 8, wherein the aromatic compound has at least one substituent.

Item 10, the co-crystal of item 9, wherein the at least one substituent is selected from-OH, -NH₂Alkyl, -NO₂And a carbonyl-containing moiety.

The co-crystal of item 11, item 10, wherein the carbonyl-containing moiety is an organic acid moiety.

Item 12, the co-crystal of item 11, wherein the organic acid moiety is selected from C₁-C₄An organic acid.

Item 13, the co-crystal of item 12, wherein the organic acid moiety is-COOH.

The co-crystal of item 14, item 10, wherein the at least one substituent is an-OH moiety.

Item 15, the co-crystal of item 10, wherein the at least one substituent is selected from an ester and an alkyl moiety.

Item 16, the co-crystal of item 15, wherein the ester is selected from C₁-C₅And (3) an ester.

The co-crystal of any one of items 17, 9 to 16, wherein the aromatic compound has two substituents.

The co-crystal of any one of items 18, 9-16, wherein the aromatic compound has three substituents.

The co-crystal of any one of items 19, 9-16, wherein the aromatic compound has four substituents.

Item 20, the co-crystal of item 17, wherein there are two substituents, and each substituent is independently selected from-OH, -NH ₂Alkyl, organic acids, esters and-NO₂And (4) partial.

Co-crystal of item 21, item 20, wherein the first substituent is an organic acid and the second substituent is selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial.

Item 22, the co-crystal of item 21, wherein the second substituent is-NH₂And (4) partial.

Item 23, the co-crystal of item 22, wherein the-NH₂Moieties and the organic acid moieties are ortho to each other.

Item 24, the co-crystal of item 22, wherein the-NH₂Moieties and the organic acid moiety are meta to each other.

Item 25, the co-crystal of item 22, wherein the-NH₂Moieties and the organic acid moiety are para to each other.

Item 26, the co-crystal of item 21, wherein the second substituent is-NO₂And (4) partial.

Item 27, the co-crystal of item 26, wherein the-NO₂Moieties and the organic acid moieties are ortho to each other.

Item 28, the co-crystal of item 26, wherein the-NO₂Moieties and the organic acid moiety are meta to each other.

Item 29, the method of item 26Wherein said-NO is₂Moieties and the organic acid moiety are para to each other.

Item 30, the co-crystal of item 21, wherein the second substituent is an-OH moiety.

Item 31, the co-crystal of item 30, wherein the-OH moiety and the organic acid moiety are ortho to each other.

Item 32, the co-crystal of item 30, wherein the-OH moiety and the organic acid moiety are meta to each other.

Item 33, the co-crystal of item 30, wherein the-OH moiety and the organic acid moiety are para to each other.

Item 34, the co-crystal of item 21, wherein the second substituent is an alkyl moiety.

Item 35, the co-crystal of item 34, wherein the alkyl moiety and the organic acid moiety are ortho to each other.

Item 36, the co-crystal of item 34, wherein the alkyl moiety and the organic acid moiety are meta to each other.

Item 37, the co-crystal of item 34, wherein the alkyl moiety and the organic acid moiety are para to each other.

The co-crystal of item 38, item 21, wherein the second substituent is an organic acid moiety.

Item 39, the co-crystal of item 38, wherein the two organic acid substituents are ortho to each other.

A co-crystal of item 40, according to item 38, wherein the two organic acid moieties are meta to each other.

Item 41, the co-crystal of item 38, wherein the two organic acid moieties are aligned with each other.

Item 42, the co-crystal of item 21, wherein the second substituent is an ester moiety.

Item 43, the co-crystal of item 42, wherein the ester moiety and the organic acid moiety are ortho to each other.

The co-crystal of item 44, item 42, wherein the ester moiety and the organic acid moiety are meta to each other.

Item 45, the co-crystal of item 42, wherein the ester moiety and the organic acid moiety are para to each other.

Item 46, the co-crystal of item 18, wherein there are three substituents, and each substituent is independently selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial.

Item 47, the co-crystal of item 46, wherein the first substituent is-OH.

Item 48, the co-crystal of item 47, wherein the second and third substituents are-OH.

The co-crystal of item 49, item 46, wherein the first substituent is an organic acid moiety.

Item 50, the co-crystal of item 49, wherein the second and third substituents are organic acid moieties.

The co-crystal of any one of items 51 and 49-50, wherein the organic acid moiety is-COOH.

Item 52, the co-crystal of item 19, wherein there are four substituents, and each substituent is independently selected from-OH, -NH ₂Alkyl, organic acids, esters and-NO₂And (4) partial.

Item 53, the co-crystal of item 52, wherein the first substituent is an ester moiety or an organic acid moiety.

The co-crystal of item 54, item 53, wherein the ester is a methyl ester.

A co-crystal of item 55, item 53, wherein the ester is an ethyl ester.

Item 56, the co-crystal of any one of items 53-55, wherein the second substituent is an-OH moiety.

Item 57, the co-crystal of any one of items 53-55, wherein the second, third, and fourth substituents are each an-OH moiety.

Item 58, the co-crystal of any one of items 7-22, wherein the aromatic compound is polycyclic.

Item 59, the co-crystal of any one of items 26, 30, 34, 42, 46, and 49-57, wherein the aromatic compound is polycyclic.

The co-crystal of any of items 60 to 58, wherein the polycyclic aromatic compound is two six-membered rings.

Item 61, the co-crystal of any one of items 58-59, wherein the polycyclic aromatic compound is one six-membered ring and one five-membered ring.

The co-crystal of item 62, any of items 7-61, wherein the ring atoms of the aromatic compound are all carbon.

Item 63, the co-crystal of any one of items 7-61, wherein at least one ring atom of the aromatic compound is not carbon.

Item 64, the co-crystal of item 63, wherein at least one ring atom is nitrogen.

The co-crystal of any one of items 65 to 58, wherein there is one substituent on the polycyclic aromatic compound.

Item 66, the co-crystal of item 65, wherein the substituent is selected from C₁-C₄An organic acid moiety.

Item 67 the co-crystal of item 66, wherein the acid is C₂An acid moiety.

Item 68 the crystalline compound of any one of items 4-5, wherein the aromatic compound is substituted.

Item 69, the crystalline compound of item 68, wherein there is at least one substituent.

Item 70, the crystalline compound of item 69, wherein the at least one substituent is selected from-OH, -NH₂Alkyl, -NO₂And a carbonyl-containing moiety.

Item 71, the crystalline compound of item 70, wherein the at least one substituent is an organic acid moiety.

Item 72, the crystalline compound of item 71, wherein the organic acid is selected from C₁-C₄An organic acid moiety.

Item 73 the crystalline compound of item 72, wherein the organic acid moiety is-COOH.

Item 74 the crystalline compound of item 70, wherein the at least one substituent is an-OH moiety.

Item 75, the crystalline compound of item 70, wherein the at least one substituent is selected from an ester and an alkyl moiety.

Item 76 the crystalline compound of item 75, wherein the ester is selected from C₁-C₄And (3) an ester.

Item 77, the crystalline compound of any one of items 69-76, wherein the aromatic compound has two substituents.

Item 78, the crystalline compound of any one of items 69 to 76, wherein the aromatic compound has three substituents.

Item 79, the crystalline compound of any one of items 69-76, wherein the aromatic compound has four substituents.

Item 80, the crystalline compound of item 77, wherein there are two substituents, and each substituent is independently selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial.

Item 81, the crystalline compound of item 80, wherein the first substituent is an organic acid and the second substituent is selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial.

Item 82, the crystalline compound of item 81, wherein the second substituent is-NH ₂And (4) partial.

Item 83 the crystalline compound of item 80, wherein the-NH₂Moieties and the organic acid moieties are ortho to each other.

Item 84, the crystalline compound of item 80, wherein the-NH₂Moieties and the organic acid moiety are meta to each other.

Item 85, the crystalline compound of item 80, wherein the-NH₂Moieties and the organic acid moiety are para to each other.

Item 86 the crystalline compound of item 81, wherein the second substituent is-NO₂And (4) partial.

Item 87, the crystalline compound of item 86, wherein the-NO₂Moieties and the organic acid moieties are ortho to each other.

Item 88 the crystalline compound of item 86, wherein the-NO₂Moieties and the organic acid moiety are meta to each other.

Item 89, the crystalline compound of item 86, wherein the-NO₂Moieties and the organic acid moiety are para to each other.

Item 90, the crystalline compound of item 81, wherein the second substituent is an-OH moiety.

Item 91, the crystalline compound of item 90, wherein the-OH moiety and the organic acid moiety are ortho to each other.

Item 92, the crystalline compound of item 90, wherein the-OH moiety and the organic acid moiety are meta to each other.

Item 93, the crystalline compound of item 90, wherein the-OH moiety and the organic acid moiety are para to each other.

Item 94, the crystalline compound of item 81, wherein the second substituent is an alkyl moiety.

Item 95, the crystalline compound of item 94, wherein the alkyl moiety and the organic acid moiety are ortho to each other.

Item 96, the crystalline compound of item 94, wherein the alkyl moiety and the organic acid moiety are meta to each other.

Item 97, the crystalline compound of item 94, wherein the alkyl moiety and the organic acid moiety are para to each other.

Item 98, the crystalline compound of item 81, wherein the second substituent is an organic acid moiety.

Item 99, the crystalline compound of item 98, wherein the two organic acid moieties are ortho to each other.

Item 100, the crystalline compound of item 98, wherein the two organic acid moieties are meta to each other.

Item 101, the crystalline compound of item 98, wherein the two organic acid moieties are para to each other.

Item 102, the crystalline compound of item 81, wherein the second substituent is an ester moiety.

Item 103, the crystalline compound of item 102, wherein the ester moiety and the organic acid moiety are ortho to each other.

Item 104, the crystalline compound of item 102, wherein the ester moiety and the organic acid moiety are meta to each other.

Item 105, the crystalline compound of item 102, wherein the ester moiety and the organic acid moiety are para to each other.

Item 106, the crystalline compound of any one of items 77-78, wherein there are three substituents, and each substituent is independently selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial.

Item 107, the crystalline compound of item 106, wherein the first substituent is an-OH moiety.

Item 108, the crystalline compound of item 107, wherein the second and third substituents are-OH moieties.

Item 109, the crystalline compound of item 106, wherein the first substituent is an organic acid moiety.

Item 110, the crystalline compound of item 106, wherein the second and third substituents are organic acid moieties.

Item 111, the crystalline compound of any one of items 109-110, wherein the organic acid moiety is-COOH.

Item 112, the crystalline compound of any one of items 77-79, wherein there are four substituents, and each substituent is independently selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial.

Item 113, the crystalline compound of item 112, wherein the first substituent is an ester.

Item 114, the crystalline compound of item 113, wherein the ester is a methyl ester.

Item 115 the crystalline compound of item 113, wherein the ester is an ethyl ester.

Item 116, the crystalline compound of any one of items 113-115, wherein the second substituent is an-OH moiety.

Item 117, the crystalline compound of any one of items 113-115, wherein the second, third, and fourth substituents are each an-OH moiety.

Item 118, the crystalline compound of any one of items 4-5, wherein the aromatic compound is polycyclic.

Item 119, the crystalline compound of any one of items 68-90, wherein the aromatic compound is polycyclic.

Item 120, the crystalline compound of any one of items 118-119, wherein the polycyclic aromatic is two six-membered rings.

Item 121, the crystalline compound of any one of items 118-119, wherein the polycyclic aromatic is one six-membered ring and one five-membered ring.

Item 122, the crystalline compound of any one of items 4-5 or 68-121, wherein the ring atoms of the aromatic compound are all carbon.

Item 123, the crystalline compound of any one of items 4-5 or 68-121, wherein at least one ring atom is not carbon.

Item 124, the crystalline compound of item 123, wherein at least one ring atom is nitrogen.

Item 125, the crystalline compound of any one of items 118-124, wherein there is one substituent on the polycyclic aromatic compound.

Item 126 the crystalline compound of item 125, wherein the substituent is selected from C₁-C₄An organic acid moiety.

Item 127, the crystalline compound of item 126, wherein theThe organic acid moiety being C₂And (4) acid.

Item 128, a crystalline compound comprising fasorasitan and 4-aminobenzoic acid.

Item 129, the crystalline compound of item 128, wherein the fasorasitan is R-fasorasitan.

Item 130, co-crystal of fasorasitan and 4-aminobenzoic acid.

Item 131, eutectic of R-fasorasiracetam and 4-aminobenzoic acid.

Item 132, the co-crystal of item 130, wherein the stoichiometric ratio of fasorracetam to 4-aminobenzoic acid is about 1: 1.

Item 133, the co-crystal of item 130, wherein in a unit cell of the co-crystal, a molar ratio of fasorasitan to 4-aminobenzoic acid is 1: 1.

item 134, the co-crystal of item 131, wherein the stoichiometric ratio of R-fasorasitan to 4-aminobenzoic acid is about 1: 1.

item 135, the co-crystal of item 131, wherein in a unit cell of the co-crystal, a molar ratio of R-fasorasitan to 4-aminobenzoic acid is 1: 1.

item 136, the co-crystal of any one of items 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 6.5 ° 2 Θ.

Item 137, the co-crystal of any of items 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 10.5 ° 2 Θ.

Item 138, the co-crystal of any of items 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 11.3 ° 2 Θ.

Item 139, the co-crystal of any one of items 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 12.0 ° 2 Θ.

Item 140, the co-crystal of any one of items 131 or 134-135, wherein the X-ray powder diffraction of the co-crystal comprises one or more peaks selected from peaks at about 6.5 ° 2 Θ, about 10.5 ° 2 Θ, about 11.3 ° 2 Θ, and about 12.0 ° 2 Θ.

Item 141, the co-crystal of any one of items 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 6.5 ° 2 Θ, about 10.5 ° 2 Θ, about 11.3 ° 2 Θ, about 12.0 ° 2 Θ, about 13.4 ° 2 Θ, about 13.7 ° 2 Θ, about 17.4 ° 2 Θ, about 18.1 ° 2 Θ, about 18.7 ° 2 Θ, about 19.6 ° 2 Θ, about 20.6 ° 2 Θ, about 21.1 ° 2 Θ, about 21.4 ° 2 Θ, about 22.8 ° 2 Θ, about 23.2 ° 2 Θ, and about 23.7 ° 2 Θ.

Item 142, the co-crystal of any one of items 131 or 134-135, wherein the melting temperature of the co-crystal is about 114 ℃.

Item 143 the co-crystal of item 142, wherein the onset melting temperature is measured by differential scanning calorimetry.

Item 144, the co-crystal of any of items 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 6.5 ° 2 Θ and an onset melting temperature of about 114 ℃.

Item 145, the co-crystal of any of items 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 10.5 ° 2 Θ and an onset melting temperature of about 114 ℃.

Item 146, the co-crystal of any of items 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 11.3 ° 2 Θ and an onset melting temperature of about 114 ℃.

Item 147, the co-crystal of any of items 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 12.0 ° 2 Θ and an onset melting temperature of about 114 ℃.

Item 148, the co-crystal of any of items 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks at 6.5 ° 2 Θ, about 10.5 ° 2 Θ, about 11.3 ° 2 Θ, or about 12.0 ° 2 Θ, and an onset melting temperature of about 114 ℃.

Item 149, the co-crystal of any one of items 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 6.5 ° 2 Θ, about 10.5 ° 2 Θ, about 11.3 ° 2 Θ, about 12.0 ° 2 Θ, about 13.4 ° 2 Θ, about 13.7 ° 2 Θ, about 17.4 ° 2 Θ, about 18.1 ° 2 Θ, about 18.7 ° 2 Θ, about 19.6 ° 2 Θ, about 20.6 ° 2 Θ, about 21.1 ° 2 Θ, about 21.4 ° 2 Θ, about 22.8 ° 2 Θ, about 23.2 ° 2 Θ, and about 23.7 ° 2 Θ, and an initial melting temperature of the co-crystal is about 114 ℃.

Item 150, the co-crystal of any of items 131 or 134-135, wherein the X-ray powder diffraction pattern of the co-crystal is substantially the same as fig. 1.

Item 151, the co-crystal of any of items 131 or 134-135, wherein the differential scanning calorimetry thermogram is substantially the same as figure 4.

Item 152, the co-crystal of item 130, wherein the fasorracetam is S-fasorracetam.

Item 153, a pharmaceutical composition comprising a co-crystal of fasorasitan and 4-aminobenzoic acid and one or more pharmaceutically acceptable excipients.

Item 154, the pharmaceutical composition of item 153, wherein the fasorracetam is R-fasorracetam.

Item 155, the pharmaceutical composition of item 153, wherein an X-ray powder diffraction pattern of the pharmaceutical composition comprises a peak at about 6.5 ° 2 Θ.

Item 156, the pharmaceutical composition of item 154, wherein the X-ray powder diffraction pattern comprises one or more peaks selected from peaks at about 6.5 ° 2 Θ, about 10.5 ° 2 Θ, about 11.3 ° 2 Θ, about 12.0 ° 2 Θ, about 13.4 ° 2 Θ, about 13.7 ° 2 Θ, about 17.4 ° 2 Θ, about 18.1 ° 2 Θ, about 18.7 ° 2 Θ, about 19.6 ° 2 Θ, about 20.6 ° 2 Θ, about 21.1 ° 2 Θ, about 21.4 ° 2 Θ, about 22.8 ° 2 Θ, about 23.2 ° 2 Θ, and about 23.7 ° 2 Θ.

An item 157, the pharmaceutical composition of item 154, wherein the R-fasoracetam co-crystal has an onset melting point temperature of about 114 ℃.

Item 158, a crystalline compound comprising fasorasitan and trimesic acid.

Item 159, the crystalline compound of item 158, wherein the fasorracetam is R-fasorracetam.

Item 160, co-crystal of fasoracetam and trimesic acid.

Item 161, eutectic crystal of R-fasoracetam and trimesic acid.

A co-crystal of item 162, item 160, wherein the stoichiometric ratio of fasoracetam to trimesic acid is about 1: 1.

item 163, the co-crystal of item 160, wherein in the unit cell of the co-crystal, the molar ratio of fasorasitan to trimesic acid is 1: 1.

a co-crystal of item 164, wherein the stoichiometric ratio of R-fasoracetam to trimesic acid is about 1: 1.

item 165 the co-crystal of item 161, wherein in the unit cell of the co-crystal, the molar ratio of R-fasorasitan to trimesic acid is 1: 1.

item 166, the co-crystal of any one of items 161 or 164-165, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 9.7 ° 2 Θ.

Item 167, the co-crystal of any of items 161 or 164-165, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 9.7 ° 2 Θ, about 10.9 ° 2 Θ, about 2 ° 2 Θ, about 11.4 ° 2 Θ, about 14.6 ° 2 Θ, about 16.5 ° 2 Θ, about 17.5 ° 2 Θ, about 18.6 ° 2 Θ, about 2 ° 2 Θ, about 19.4 ° 2 Θ, about 2 ° 2 Θ, about 19.8 ° 2 Θ, about 21.8 ° 2 Θ, about 23.5 ° 2 Θ, about 26.7 ° 2 Θ, and about 27.3 ° 2 Θ.

Item 168, the co-crystal of any of items 161 or 164-165, wherein the starting melting temperature of the co-crystal is about 96 ℃.

Item 169, the co-crystal of item 168, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 9.7 ° 2 Θ, about 10.9 ° 2 Θ, about 2 ° 2 Θ, about 11.4 ° 2 Θ, about 14.6 ° 2 Θ, about 16.5 ° 2 Θ, about 17.5 ° 2 Θ, about 18.6 ° 2 Θ, about 2 ° 2 Θ, about 19.4 ° 2 Θ, about 2 ° 2 Θ, about 19.8 ° 2 Θ, about 21.8 ° 2 Θ, about 23.5 ° 2 Θ, about 26.7 ° 2 Θ, and about 27.3 ° 2 Θ.

Item 170, the co-crystal of any one of items 161 or 164-165, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 51.

The co-crystal of item 171, any of items 161 or 164-165, wherein the DSC thermogram of the co-crystal is substantially the same as figure 54.

Item 172, a crystalline compound comprising R-fasorasitan and R-ibuprofen.

Item 173, co-crystal of R-fasorasitan and R-ibuprofen.

A co-crystal of item 174, wherein the stoichiometric ratio of R-fasorasitan to R-ibuprofen is about 1: 1.

item 175, the co-crystal of item 173, wherein in the unit cell of the co-crystal, the molar ratio of R-fasorasitan to R-ibuprofen is 1: 1.

Item 176, the co-crystal of any one of items 173-175, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.6 ° 2 Θ, about 10.5 ° 2 Θ, about 11.2 ° 2 Θ, about 12.3 ° 2 Θ, about 17.4 ° 2 Θ, about 20.1 ° 2 Θ, and about 20.6 ° 2 Θ.

Item 177, the co-crystal of any one of items 173-175, wherein the co-crystal has an initial melting temperature of about 115 ℃.

Item 178, the co-crystal of item 176, wherein the co-crystal has an initial melting temperature of about 115 ℃.

Item 179, the co-crystal of any of items 173-175, having an X-ray powder diffraction pattern substantially the same as figure 57.

A co-crystal of any one of clauses 173-175, having a DSC thermogram substantially the same as figure 61, item 180.

Item 181, a crystalline compound comprising fasoraferacetam and phloroglucinol.

The crystalline compound of item 182, wherein the fasorracetam is R-fasorracetam.

Item 183, monohydrate co-crystal of fasorasitan and phloroglucinol.

Item 184, monohydrate co-crystal of R-fasorasitan and phloroglucinol.

Item 185, the co-crystal of item 183, wherein fasorexiptan: phloroglucinol: the stoichiometric ratio of water is about 1: 1.

Item 186, the co-crystal of item 183, wherein in a unit cell of the co-crystal, fasorasitan: phloroglucinol: the molar ratio of water is 1: 1: 1.

item 187, the co-crystal of item 184, wherein the stoichiometric ratio of R-fasorasitan to phloroglucinol is about 1: 1.

item 188, the co-crystal of item 184, wherein in a unit cell of the co-crystal, a molar ratio of R-fasorasitan to phloroglucinol is 1: 1.

item 189, the co-crystal of any one of items 184 or 187-188, wherein an X-ray powder diffraction pattern of the co-crystal has one or more peaks selected from peaks at about 6.9 ° 2 Θ, about 10.3 ° 2 Θ, about 15.3 ° 2 Θ, about 16.2 ° 2 Θ, about 17.3 ° 2 Θ, about 21.6 ° 2 Θ, about 22.6 ° 2 Θ, and about 25.3 ° 2 Θ.

Item 190, the co-crystal of any of items 184 or 187-188, having an onset of melting temperature of about 58 ℃.

Item 191, the co-crystal of item 189, having an onset of melting temperature of about 58 ℃.

Item 192, the co-crystal of any of items 184 or 187-188, having an X-ray powder diffraction pattern substantially the same as figure 72.

Item 193, a crystalline compound comprising fasorasitan and methyl-3, 4, 5-trihydroxybenzoate.

Item 194, the crystalline compound of item 193, wherein the fasorracetam is R-fasorracetam.

Item 195, a monohydrate co-crystal of fasorasitan and methyl-3, 4, 5-trihydroxybenzoate.

Project 196, a monohydrate co-crystal of R-fasorasitan and methyl-3, 4, 5-trihydroxybenzoate.

Item 197, the co-crystal of item 195, wherein the stoichiometric ratio of fasorasitan to methyl-3, 4, 5-trihydroxybenzoate is about 1: 1.

item 198, the co-crystal of item 195, wherein, in a unit cell of the co-crystal, a molar ratio of fasorasitan to methyl-3, 4, 5-trihydroxybenzoate is 1: 1.

item 199, the co-crystal of item 196, wherein the stoichiometric ratio of R-fasorasitan to methyl-3, 4, 5-trihydroxybenzoate is about 1: 1.

item 200, the co-crystal of item 196, wherein, in a unit cell of the co-crystal, a molar ratio of R-fasorasitan to methyl-3, 4, 5-trihydroxybenzoate is 1: 1.

item 201, the co-crystal of any one of items 196 or 199-200, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.7 ° 2 Θ, about 10.6 ° 2 Θ, about 11.3 ° 2 Θ, about 12.7 ° 2 Θ, about 16.6 ° 2 Θ, about 18.9 ° 2 Θ, about 20.6 ° 2 Θ, about 24.3 ° 2 Θ, and about 25.0 ° 2 Θ.

Item 202, the co-crystal of any of items 196 or 199-200, wherein the X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 75.

Item 203, a crystalline compound comprising fasoraferacetam and ethyl gallate.

Item 204, the crystalline compound of item 203, wherein the fasorracetam is R-fasorracetam.

Item 205, co-crystal of fasorasitan and ethyl gallate.

Item 206, co-crystal of R-fasorasitan and ethyl gallate.

Item 207, the co-crystal of item 205, wherein the stoichiometric ratio of fasoraferacetam to ethyl gallate is about 1:1 or about 1: 2.

item 208, the co-crystal of item 205, wherein, in a unit cell of the co-crystal, the molar ratio of fasorasitan to ethyl gallate is 1:1 or 1: 2.

a co-crystal of item 209, the item 206, wherein the stoichiometric ratio of R-fasorasitan to ethyl gallate is about 1:1 or about 1: 2.

item 210, the co-crystal of item 206, wherein, in a unit cell of the co-crystal, the molar ratio of R-fasorasitan to ethyl gallate is 1:1 or 1: 2.

item 211, the co-crystal of any one of items 206 or 209-210, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.8 ° 2 Θ, about 11.3 ° 2 Θ, about 12.4 ° 2 Θ, about 15.5 ° 2 Θ, about 15.8 ° 2 Θ, about 18.2 ° 2 Θ, about 19.4 ° 2 Θ, about 22.0 ° 2 Θ, and about 24.8 ° 2 Θ, wherein, in the unit cell, the molar ratio of R-fraxidin to ethyl gallate is 1:1, or the stoichiometric ratio of fraxidin to ethyl gallate is about 1: 1.

A co-crystal of item 212, wherein the molar ratio of R-fasorasitan to ethyl gallate in the unit cell is 1: 1.

item 213, the co-crystal of item 211, wherein the co-crystal has an onset melting temperature of about 112 ℃.

Item 214, the co-crystal of item 212, wherein the co-crystal has an onset melting point temperature of about 112 ℃.

Item 215, the co-crystal of item 206, wherein the X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.8 ° 2 Θ, about 7.2 ° 2 Θ, about 14.8 ° 2 Θ, about 20.4 ° 2 Θ, about 21.9 ° 2 Θ, and about 23.5 ° 2 Θ, wherein, in a unit cell of the co-crystal, the molar ratio of R-fasoracetam to ethyl gallate is 1: 2.

item 216, the co-crystal of item 206, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.8 ° 2 Θ, about 7.2 ° 2 Θ, about 14.8 ° 2 Θ, about 20.4 ° 2 Θ, about 21.9 ° 2 Θ, and about 23.5 ° 2 Θ, wherein the stoichiometric ratio of R-fasorasitan to ethyl gallate is about 1: 2.

item 217, a dihydrate co-crystal, wherein the stoichiometric ratio of fasorasitan to ethyl gallate is about 1: 2.

Item 218, a dihydrate co-crystal, wherein, in the unit cell of the co-crystal, the molar ratio of fasorasitan to ethyl gallate is 1: 2.

item 219, the dihydrate co-crystal of any of items 217-218, wherein the X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 8.8 ° 2 Θ, about 11.2 ° 2 Θ, about 19.4 ° 2 Θ, about 19.9 ° 2 Θ, and about 24.1 ° 2 Θ.

Item 220, the co-crystal of any of items 217-219, wherein the co-crystal has an onset of melting temperature of about 106 ℃ as measured by DSC.

Item 221, the co-crystal of any one of items 206 or 209-210, wherein the X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 79.

Item 222, the co-crystal of any one of items 206 or 209-210, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 86.

Item 223, the co-crystal of any of items 217-218, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 88.

Item 224, the co-crystal of any one of items 217-218, wherein the fasorracetam is R-fasorracetam.

Item 225, a crystalline compound comprising fasoraferacetam and phthalic acid.

The crystalline compound of item 226, wherein the fasorracetam is R-fasorracetam.

Item 227, co-crystal of fasorasitan and phthalic acid.

Item 228, co-crystal of R-fasorasitan and phthalic acid.

Item 229, the co-crystal of item 227, wherein the stoichiometric ratio of fasoraferacetam to phthalic acid is about 1: 1.

item 230, the co-crystal of item 227, wherein in the unit cell of the co-crystal, the molar ratio of fasorasitan to phthalic acid is 1: 1.

a co-crystal of item 231, item 228, wherein the stoichiometric ratio of R-fasorasitan to phthalic acid is about 1: 1.

item 232, the co-crystal of item 228, wherein in a unit cell of the co-crystal, a molar ratio of R-fasorasitan to phthalic acid is 1: 1.

item 233, the co-crystal of any one of items 228 or 231-232, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 6.1 ° 2 Θ, about 12.4 ° 2 Θ, about 15.1 ° 2 Θ, about 15.8 ° 2 Θ, about 18.1 ° 2 Θ, about 19.9 ° 2 Θ, and about 23.3 ° 2 Θ.

Item 234, the co-crystal of any one of items 228 or 231-232, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 64.

Item 235, a crystalline compound comprising fasoraferacetam and 6-hydroxy-2-naphthoic acid.

The crystalline compound of item 236, wherein the fasorracetam is R-fasorracetam.

Eutectic of item 237, fasorasitan and 6-hydroxy-2-naphthoic acid.

Item 238, co-crystal of R-fasorasitan and 6-hydroxy-2-naphthoic acid.

Item 239, the co-crystal of item 238, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 11.2 ° 2 Θ.

Item 240, the co-crystal of item 238, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 11.2 ° 2 Θ, about 14.9 ° 2 Θ, about 15.7 ° 2 Θ, about 20.1 ° 2 Θ, about 21.1 ° 2 Θ, about 23.6 ° 2 Θ, about 24.1 ° 2 Θ, about 25.0 ° 2 Θ, and about 25.5 ° 2 Θ.

Item 241, the co-crystal of any of items 238-240, wherein the starting melting temperature of the co-crystal is about 120 ℃.

Item 242, the co-crystal of item 238 or 241, wherein the X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 93.

Item 243, the co-crystal of any one of items 238-240 or 242, wherein a DSC thermogram of the co-crystal is substantially the same as figure 97.

Item 244, a crystalline compound comprising fasorasitan and 4-nitrobenzoic acid.

Item 245, the crystalline compound of item 244, wherein the fasorracetam is R-fasorracetam.

Item 246, co-crystal of fasoracetam and 4-nitrobenzoic acid.

Item 247, co-crystal of R-fasorasitan and 4-nitrobenzoic acid.

Item 248, the co-crystal of item 246, wherein the stoichiometric ratio of fasoracetam to 4-nitrobenzoic acid is about 1: 2.

item 249, the co-crystal of item 246, wherein in the unit cell of the co-crystal, the molar ratio of fasoracetam to 4-nitrobenzoic acid is 1: 2.

item 250, the co-crystal of item 247, wherein the stoichiometric ratio of R-fasorasitan to 4-nitrobenzoic acid is about 1: 2.

item 251, the co-crystal of item 247, wherein in the unit cell of the co-crystal, the molar ratio of R-fasorasitan to 4-nitrobenzoic acid is 1: 2.

item 252, the co-crystal of any one of items 247 or 250-251, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 6.5 ° 2 Θ, about 6.7 ° 2 Θ, about 8.9 ° 2 Θ, about 14.5 ° 2 Θ, about 15.6 ° 2 Θ, about 17.9 ° 2 Θ, about 18.6 ° 2 Θ, about 19.8 ° 2 Θ, about 23.4 ° 2 Θ, and about 26.4 ° 2 Θ.

Item 253, the co-crystal of any one of items 247 or 250-251, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 100.

Item 254, the co-crystal of any one of items 247 or 250-253, wherein the initial melting temperature of the co-crystal is about 146 ℃.

Item 255, the co-crystal of any one of items 247 or 250-253, wherein a DSC thermogram of the co-crystal is substantially the same as figure 105.

Item 256, a crystalline compound comprising fasorasiracetam and 2-indole-3-acetic acid.

Item 257, the crystalline compound of item 256, wherein the fasorracetam is R-fasorracetam.

Item 258, co-crystal of fasorasitan and 2-indole-3-acetic acid.

Co-crystal of item 259, R-fasorasiracetam and 2-indole-3-acetic acid.

Item 260, the co-crystal of item 259, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 11.8 ° 2 Θ.

Item 261, the co-crystal of item 259, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.3 ° 2 Θ, about 7.9 ° 2 Θ, about 10.7 ° 2 Θ, about 11.8 ° 2 Θ, about 14.7 ° 2 Θ, about 15.8 ° 2 Θ, about 18.0 ° 2 Θ, about 21.9 ° 2 Θ, about 23.1 ° 2 Θ, and about 23.5 ° 2 Θ.

Item 262, the co-crystal of any of items 259-261, wherein the co-crystal has an initial melting temperature of about 69 ℃.

Item 263, the co-crystal of item 259, wherein the X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 107.

Item 264, the co-crystal of any one of items 259-261, or 263, wherein a DSC thermogram of the co-crystal is substantially the same as figure 111.

Item 265 the co-crystal of item 1, wherein the co-crystal former is non-aromatic and comprises a compound selected from-NH₂、-NO₂Organic acids such as-COOH, -C (═ O) -X, -C (═ O) -OR₁At least one moiety of (1), wherein R₁Is an alkyl group and X is a nitrogen-containing moietyAnd (4) dividing.

Item 266, the co-crystal of item 265, wherein R₁Is C₁To C₁₂An alkyl group.

Clause 267, the eutectic of clause 265 or 266, wherein the non-aromatic eutectic former comprises at least one NH₂。

Item 268, the eutectic of any one of items 265-267, wherein the non-aromatic eutectic former comprises two NH₂And (4) partial.

Item 269, the co-crystal of any one of items 265-268, wherein the fasorracetam is R-fasorracetam.

Item 270, the co-crystal of item 1, wherein the co-crystal former is non-aromatic and comprises at least one-C (O) NR ₂R₃Moiety wherein R₂And R₃Independently selected from H, alkyl, substituted alkyl and C₁To C₅An alcohol.

Item 271, the co-crystal of item 270, wherein the co-crystal former comprises one — C (O) NR₂R₃And (4) partial.

Item 272, the co-crystal of any of items 270-271, wherein alkyl and substituted alkyl each independently comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbons.

Item 273, the co-crystal of item 272, wherein the substituted alkyl is substituted with at least one of a halogen or a nitrile.

Item 274, the co-crystal of item 273, wherein the halogen is bromine.

Item 275, the co-crystal of any of items 270-274, wherein the alcohol is C₂An alcohol.

Item 276, the co-crystal of any of items 270-274, wherein the alkyl is C₁₁An alkyl group.

Item 277, the co-crystal of item 1, wherein the co-crystal former is non-aromatic and comprises at least one-C (O) NX moiety, wherein X is ═ N-R₄Wherein R is₄Is a carbonyl containing moiety.

Item 278, the co-crystal of item 277, wherein the carbonyl-containing moiety is an amide.

Item 279, the co-crystal of any of items 270-278, wherein the fasorracetam is R-fasorracetam.

Item 280, a crystalline compound comprising fasoraferacetam and urea.

Item 281, the crystalline compound of item 280, wherein the fasoracetam is R-fasoracetam.

Item 282, co-crystal of fasorasitan and urea.

Item 283, eutectic of R-fasorasiracetam and urea.

Item 284, the co-crystal of item 282, wherein the stoichiometric ratio of fasoraferacetam to urea is about 1: 1.

item 285 the co-crystal of item 282, wherein in a unit cell of the co-crystal, a molar ratio of fasorracetam to urea is 1: 1.

item 286, the co-crystal of item 283, wherein the stoichiometric ratio of R-fasorasitan to urea is about 1: 1.

item 287, the co-crystal of item 283, wherein a molar ratio of R-fasorasitan to urea in a unit cell of the co-crystal is 1: 1.

item 288, the co-crystal of any of items 283 or 286-287, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 10.4 ° 2 Θ.

Item 289, the co-crystal of any of items 283 or 286-287, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 14.0 ° 2 Θ or 14.1 ° 2 Θ.

Item 290, the co-crystal of any one of items 283 or 286-287, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 10.8 ° 2 Θ.

Item 291, eutectic of R-fasorasiracetam and urea type a.

Item 292, the co-crystal of R-fasorasiracetam and urea of any one of items 282-290.

Item 293, the co-crystal of item 291, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 12.2 ° 2 Θ.

Item 294, the co-crystal of item 291, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 16.1 ° 2 Θ.

Item 295, the co-crystal of item 291, wherein an X-ray powder diffraction pattern of the co-crystal comprises one peak at about 12.2 ° θ, and one or more peaks selected from the group consisting of peaks at about 10.4 ° 2 θ, about 10.8 ° 2 θ, about 14.1 ° 2 θ, about 16.1 ° 2 θ, about 18.9 ° 2 θ, about 22.3 ° 2 θ, and about 22.9 ° 2 θ.

Item 296, the co-crystal of item 291, wherein an X-ray powder diffraction pattern of the co-crystal comprises one peak at about 16.1 ° 2 Θ, and one or more peaks selected from the group consisting of peaks at about 10.4 ° 2 Θ, about 10.8 ° 2 Θ, about 12.2 ° 2 Θ, about 14.1 ° 2 Θ, about 18.9 ° 2 Θ, about 22.3 ° 2 Θ, and about 22.9 ° 2 Θ.

Item 297, the co-crystal of item 291, having an X-ray powder diffraction pattern substantially the same as figure 44.

Item 298, the co-crystal of any one of items 291 or 293-297, wherein the melting onset temperature of the co-crystal is about 91 ℃.

Item 299 the co-crystal of item 298, wherein the melting temperature is measured with DSC.

Item 300, the co-crystal of item 299, wherein a DSC thermogram of the co-crystal is substantially the same as figure 47.

Item 301, the co-crystal of item 282, wherein the fasorracetam is S-fasorracetam.

Item 302, a pharmaceutical composition comprising a co-crystal of fasoraferacetam and urea and one or more pharmaceutically acceptable excipients.

Item 303, the pharmaceutical composition of item 302, wherein the fasorracetam is R-fasorracetam.

Item 304, the pharmaceutical composition of any one of items 302-303, wherein an X-ray powder diffraction pattern of the pharmaceutical composition comprises a peak at about 10.4 ° 2 Θ.

Item 305, the pharmaceutical composition of any one of items 302-304, wherein the composition comprises a co-crystal of any one of items 295 or 296.

Item 306, the pharmaceutical composition of any one of items 302-305, wherein the R-fasoracetam co-crystal has an initial melting point temperature of about 91 ℃.

Item 307, eutectic form B of R-fasorasitan and urea.

Item 308, the co-crystal of item 307, wherein the stoichiometry of R-fasorasitan to urea is about 1: 1.

item 309, the co-crystal of item 307, wherein in a unit cell of the co-crystal, a molar ratio of R-fasorasitan to urea is 1: 1.

item 310, the co-crystal of any one of items 307-309, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 11.4 ° 2 Θ.

Item 311, the co-crystal of any one of items 307-309, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 17.5 ° 2 Θ.

Item 312, the co-crystal of any one of items 307-309, wherein an X-ray powder diffraction pattern of the co-crystal comprises at least two peaks selected from peaks at about 14.0 ° 2 Θ, about 14.5 ° 2 Θ, and about 14.9 ° 2 Θ.

Item 313, the co-crystal of any one of items 307-309, wherein an X-ray powder diffraction pattern of the co-crystal comprises peaks at about 14.5 ° 2 Θ and about 14.9 ° 2 Θ.

Item 314, the co-crystal of any one of items 307-309, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 14.5 ° 2 Θ.

Item 315, the co-crystal of any one of items 307-309, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 14.9 ° 2 Θ.

Item 316, the co-crystal of any one of items 307-309, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 11.4 ° 2 Θ, about 14.0 ° 2 Θ, about 14.5 ° 2 Θ, about 14.9 ° 2 Θ, and about 17.5 ° 2 Θ.

Item 317, the co-crystal of any one of items 307-309, wherein an X-ray powder diffraction pattern of the co-crystal comprises one peak at about 11.4 ° 2 Θ, and one or more peaks selected from the group consisting of peaks at about 10.4 ° 2 Θ, about 14.0 ° 2 Θ, about 14.5 ° 2 Θ, about 14.9 ° 2 Θ, about 17.5 ° 2 Θ, about 18.4 ° 2 Θ, about 18.7 ° 2 Θ, about 19.4 ° 2 Θ, about 20.1 ° 2 Θ, and about 21.1 ° 2 Θ.

Item 318, the co-crystal of any of items 307-317, wherein the co-crystal has an initial melting point of about 102 ℃.

The co-crystal of item 319, item 318, wherein the onset melting point is determined by DSC.

Item 320, the co-crystal of any one of items 307-309 or 318-319, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as fig. 37.

Item 321, the co-crystal of any one of items 307 to 317 or 320, wherein the co-crystal differential scanning calorimetry thermogram is substantially the same as figure 40.

Item 322, a pharmaceutical composition comprising a form B co-crystal of fasoraferacetam and urea, and one or more pharmaceutically acceptable excipients.

Item 323, the pharmaceutical composition of item 322, wherein the fasorracetam is R-fasorracetam.

Item 324, the pharmaceutical composition of any one of items 322-323, wherein an X-ray powder diffraction pattern of the pharmaceutical composition comprises a peak at about 11.4 ° 2 Θ.

Item 325, the pharmaceutical composition of any one of items 322-323, wherein the composition has an X-ray powder diffraction pattern comprising one or more peaks, wherein the X-ray powder diffraction pattern of the co-crystal comprises one peak at about 11.4 ° 2 Θ, and one or more peaks selected from the group consisting of peaks at about 10.4 ° 2 Θ, about 14.0 ° 2 Θ, about 14.5 ° 2 Θ, about 14.9 ° 2 Θ, about 17.5 ° 2 Θ, about 18.4 ° 2 Θ, about 18.7 ° 2 Θ, about 19.4 ° 2 Θ, about 20.1 ° 2 Θ, and about 21.1 ° 2 Θ.

The pharmaceutical composition of any of clauses 326, 322-325, wherein the R-fasoracetam co-crystal has an initial melting point temperature of about 102 ℃.

The co-crystal of item 327 or item 1, wherein the co-crystal former comprises at least one carboxylic acid functional group.

Item 328, the co-crystal of item 327, wherein the fasoracetam forms a synthon of formula II with the carboxylic acid functionality of the co-crystal former.

Item 329, the co-crystal of item 1, wherein the co-crystal former comprises a compound selected from the group consisting of oxygen, nitrogen, -NH, alkyl, and- (O) COR₅At least one functional group of (1), wherein R₅Selected from hydrogen or alkyl, e.g. C₁To C₅An alkyl group.

Item 330, the co-crystal of item 329, wherein the fasorasitan and the co-crystal former form a synthon of formula III.

Item 331, the co-crystal of item 330, wherein Y is selected from the group consisting of oxygen, nitrogen, -NH, and- (O) COR₅Wherein R is₅Selected from substituted or unsubstituted alkyl groups and substituted or unsubstituted aryl groups.

Item 332, the co-crystal of item 331, wherein Y is- (O) COR₅Wherein R is₅Is a substituted or unsubstituted alkyl group.

Item 333, the co-crystal of any of items 7-22, 26, 30, 34, 42, 46, or 49-57, wherein the aromatic compound comprises an aromatic ring fused to a non-aromatic cyclic moiety.

Item 334, the co-crystal of item 333, wherein at least one non-aromatic cyclic moiety is partially saturated.

Item 335, the co-crystal of item 333, wherein there are at least two non-aromatic cyclic moieties.

Item 336, the co-crystal of item 333, wherein at least one non-aromatic cyclic moiety does not share a ring atom with the aromatic moiety.

Item 337, a pharmaceutical composition comprising a crystalline compound of any one of items 4-6, 68-129, 158-159, 172, 181-182, 193-194, 203-204, 225-226, 235-236, 244-245, 256-257, or 280-281, or a co-crystal of any one of items 1-3, 7-67, 130-152, 160-171, 173-180, 183-192, 195-202, 205-224, 227-234, 237-243, 246-255, 258-279, 282-301, 307-321, or 246-336, and one or more pharmaceutically acceptable excipients.

The crystalline compound of any one of items 338, 4-6, 68-129, 158-159, 172, 181-182, 193-194, 203-204, 225-226, 235-236, 244-245, 256-257, or 280-281, the co-crystal of any one of items 1-3, 7-67, 130-152, 160-171, 173-180, 183-192, 195-202, 205-224, 227-234, 237-243, 246-255, 258-279, 282-301, 307-321, or 327-336, or the pharmaceutical composition of any one of items 153-157, 302-306, 322-326, or 337, for use in treating attention deficit hyperactivity disorder in a human subject in need thereof.

Item 339 the use of item 338, wherein the subject has at least one Copy Number Variation (CNV) in a metabotropic glutamate receptor (mGluR) network gene.

Item 340, the co-crystal of any one of items 52-57, wherein at least one substituent is an organic acid moiety.

Item 341, the co-crystal of item 340, wherein the organic acid is a-COOH moiety.

Item 342, the pharmaceutical composition of item 302, wherein the co-crystal of R-fasorasitan and urea is selected from any one of items 283-300 or 307-321.

Item 343, a method of preparing R-fasorasitan form B: a method of co-crystallizing urea, comprising: mixing R-fasorasitan with urea in a suitable solvent to form a solution, wherein the molar amount of urea to R-fasorasitan is from about 0.7 to about 1.2; cooling the solution to form R-fasorasitan form B: eutectic of urea eutectic.

Item 344, the method of item 343, wherein the R-fasorasitan is selected from the group consisting of: the R-fasorasiracetam of type I, the R-fasorasiracetam of type II, the amorphous form of R-fasorasiracetam, and the form mixture of anhydrous R-fasorasiracetam and R-fasorasiracetam.

Item 345, the method of item 344, wherein the R-fasorasitan is type I.

Item 346, the method of items 343-345, wherein the suitable solvent is selected from the group consisting of ethyl acetate and isopropyl acetate.

Item 347, the method of item 346, wherein the suitable solvent is ethyl acetate.

Item 348, the method of item 345, wherein the ratio of the suitable solvent to each gram of form I R-fasorasitan is about 2.5ml to about 6 ml.

Item 349, the method of item 348, wherein the ratio of the suitable solvent to R-fasorasitan per gram of form I is about 3.0ml to about 5.0 ml.

Item 350, the method of item 348, wherein the ratio of the suitable solvent to each gram of form I R-fasorasitan is about 3.8ml to about 4.6 ml.

Item 351, the method of items 348-350, wherein the suitable solvent comprises ethyl acetate.

Item 352, the method of items 343-351, wherein the temperature of the solution is about 10 ℃ to 15 ℃.

Item 353, the method of items 343-351, wherein the temperature of the solution is about 15 ℃ to 20 ℃.

Item 354, the method of items 343-351, wherein the temperature of the solution is about 20 ℃ to 25 ℃.

Item 355, the method of items 343-351, wherein the temperature of the solution is about 25 ℃ to 30 ℃.

Item 356, the method of items 343-351, wherein the temperature of the solution is about 30 ℃ to 35 ℃.

Item 357, the method of items 343-351, wherein the temperature of the solution is about 35 ℃ to 40 ℃.

Item 358, the method of items 343-351, wherein the temperature of the solution is about 40 ℃ to 45 ℃.

Item 359, the method of items 343-351, wherein the temperature of the solution is about 45 ℃ to 50 ℃.

Item 360, the method of items 343-351, wherein the temperature of the solution is about 50 ℃ to 55 ℃.

Item 361, the method of items 343-351, wherein the temperature of the solution is about 55 ℃ to 60 ℃.

Item 362, the method of items 343-351, wherein the temperature of the solution is about 60 ℃ to 65 ℃.

Item 363, the method of items 343-351, wherein the temperature of the solution is about 65 ℃ to 70 ℃.

Item 364, the method of items 343-363, wherein the urea is added stepwise.

Item 365, the method of items 343-363, wherein the urea is added all at once.

Item 366, the method of items 343-365, wherein the molar amount of urea to R-fasoracetam is about 0.70, about 0.71, about 0.72, about 0.73, about 0.74, about 0.75, about 0.76, about 0.77, about 0.78, about 0.79, about 0.80, about 0.81, about 0.82, about 0.83, about 0.84, about 0.85, about 0.86, about 0.87, about 0.88, about 0.89, about 0.90, about 0.91, about 0.92, about 0.93, about 0.94, about 0.95, about 0.96, about 0.97, about 0.98, about 0.99, about 1.0, about 1.1, or about 1.2.

Item 367, the process of items 343-365, wherein the molar amount of urea to R-fasorasitan is about 0.95 to about 1.0.

Item 368, the method of items 343-367, wherein the compound of type B R-fasorasiracetam: eutectic seeds of urea eutectic are added to the solution.

Item 369, the process of items 343-368, wherein the resulting R-fasorasiracetam form B is washed after cooling: eutectic of urea eutectic.

Item 370, the method of claims 343-369, wherein the resulting R-fasorasiracetam form B: and (4) drying the eutectic of the urea eutectic.

Item 371, R-fasorasiracetam form B prepared by the method of any of items 343-370: and (4) urea eutectic crystal.

Examples

Instrument setting

The samples reported herein were analyzed using two X-ray powder diffraction (XRPD) devices. Some samples were measured using a Siemens D5000 diffractometer equipped with a Cu X-ray source operating at 40kV and 40mA and a ka radiation allowing the selection of Cu

The secondary monochromator of (1). The 2 theta values are scanned from 2 deg. to 50 deg..

Other samples were measured using a PANALYTICAL Bragg-Brentano-geometry diffractometer using Ni filtered Cu Ka radiation

The analysis was performed with an X' Celerator detector at 40kV and 40 mA. On the instrument, samples were analyzed between 4 and 50 ° 2 θ.

Peak selection was performed using the WinPLOTR tool provided in the commercially available crystallography tool software known as "fullprofsuite". Most of the peak selections are made using an automatic peak search option and its predefined default values, while some are manually selected.

DSC measurements were performed on DSC 821METTLER TOLEDO under a continuous nitrogen flow. Analysis was performed using a porous aluminum crucible. The onset temperature was determined by manually constructing a tangent to the peak and an extension of the baseline. The total enthalpy is calculated by manual peak integration by linear interpolation between the integrated initial and final temperatures. To obtain normalized enthalpy, total enthalpy is divided by total sample mass. The rate of temperature change (ramp) is typically at 5 deg.C/min.

TGA measurements were performed on a METTLER TOLEDO TGA/SDTA 851 e. The sample was placed in an open alumina crucible. All experiments were performed under a nitrogen stream.

Record on Bruker-300¹H-NMR spectrum. Relative to (CD) is reported₃)₂SO(2.5ppm) or CD₃OD (3.3ppm)¹H-NMR chemical shift. Monochromatic Mo Kalpha radiation produced using a Rigaku UltraX 18 generator

(Xenocs Fox3D mirror) on a MAR345 detector, or using monochromatic Cu Ka radiation

Single crystal X-ray Diffraction was performed on an Oxford Diffraction Xcalibur, Ruby, Gemini super diffractometer. The data images were integrated by CrysAlisPRO and applied to multiple scan absorptions already performed. In some cases, analytical numerical absorption corrections are also applied. Resolving the structure with SHELXT, then using SHELXL-2014/7 or SHELXL-2018/1 at | F²Fine trimming is performed on the I. Anisotropic refinement of the non-hydrogen atoms is performed. The hydrogen atoms are usually placed in a straddling mode with an isotropic temperature coefficient fixed at 1.2 times the U (eq) of the parent atom (1.5 times for methyl). In some cases, the hydrogen involved in the hydrogen bond can be refined freely, with the isotropic temperature coefficient fixed at 1.2 or 1.5 times the U (eq) of the parent atom. Simulated XRPD patterns were calculated from single crystal structures using the Mercury 3.3 program.

Eutectic screening

R-fasoracetam was screened against more than 60 potential co-crystal formers. Screening was performed by dry milling. Typically, an equimolar mixture of fasoracetam monohydrate form I (commercially available) and an appropriate amount of a co-crystal former, unless otherwise indicated herein, was milled in a RETSCH Mixer Mill MM 400 for 90 minutes at a beating frequency of 30Hz using stainless steel grinding beads. The resulting powder was characterized using XRPD. A common sample size is about 30mg of R-fasoracetam monohydrate form I. The formation of the co-crystal was verified by comparing the resulting XRPD pattern with the XRPD pattern of form I R-fasoracetam monohydrate and the co-crystal former. In most cases, no eutectic is produced. In the case where a eutectic was formed, further studies were conducted to analyze the eutectic.

Example 1-preparation of co-crystals of PABA and R-Fasorasitan (pulping)

The PABA was prepared as follows: r-fasoracetam 1: 1 eutectic crystal. To 15ml of ethyl acetate was added 5.03g of R-fasoracetam monohydrate form I (available from Jinnhao Hua Corp.), and 1 eq of 4-aminobenzoic acid (3.21g) was added in a closed 50ml round bottom flask at 25 ℃. The suspension was stirred for 4 days with magnetic stirring. After the first day, the slurry was seeded with the co-crystal of R-fasoracetam-PABA prepared according to example 2 and again after 3 days. After day 4 the suspension was filtered and washed 10 times with 1mL of ethyl acetate, pre-cooled to-15 ℃. The resulting eutectic powder was placed on a filter until dry. 5.63g of the material was recovered and purified by single crystal X-ray diffraction, X-ray powder diffraction, solution state ¹H-NMR, DSC and TGA analyses.

Fig. 1 provides an XRPD pattern of the co-crystal. Figure 2 is an XRPD pattern of PABA. PABA was purchased from Acros Organics. FIG. 3 is a solution state of the eutectic crystal¹H-NMR spectrum. The map shows that the ratio of R-fasorasitan to PABA is 1: 1, proton incorporation spectra.

Fig. 4 is a DSC thermogram of the co-crystal. The sample was equilibrated at 25.0 ℃ for ten minutes before warming. The ramp rate was 1 ℃ per minute and the initial temperature was 113.73 ℃. FIG. 5 is a DSC thermogram of PABA.

The TGA profile can be seen in figure 6. The sample was equilibrated at 30.0 ℃ for five minutes before warming. A ramp rate of 5 c per minute was used from 30.0 c to 350.0 c. Until temperatures above 180 ℃ were recorded, no significant weight loss was observed.

FIG. 7 is an X-ray powder diffraction of the form I R-fasoracetam monohydrate starting material used in this example 1, and FIG. 8 is the corresponding DSC thermogram of this starting material. The solubility of the co-Crystal in ethyl acetate was plotted using a Crystal16 apparatus from Technobis Crystallization Systems, and the results are plotted in fig. 10 (data collected from example 1). The samples were made of a eutectic without any addition of water or other ingredients. The sample was heated at a rate of 1 deg./15 minutes.

Example 2-preparation of co-crystals of PABA and R-fasoracetam (seed crystals)

An equimolar mixture of R-fasoracetam monohydrate type I (21.63mg) and PABA (21.48mg) from jinan haohua industries ltd was milled in RETSCH Mixer Mill MM 400 at a frequency of 30Hz for 90 minutes using stainless steel milling beads. The resulting milled mixture was characterized using X-ray powder diffraction and the diffraction pattern of the eutectic seed can be seen in fig. 11.

Example 3-preparation of co-crystals of PABA and R-Fasorasitan (1: 1) for Single Crystal analysis

A single crystal is obtained by: stoichiometric amounts of PABA (20.98mg) and R-fasoracetam monohydrate form I (available from denna haohua practice ltd) (30mg) were dissolved in ethyl acetate and the solution was slowly evaporated at room temperature to give a crystalline material which was found by analysis to be 1: 1 eutectic crystal. The resulting solution can be visualized as the ORTEP plot in fig. 13. In addition, table 4 provides single crystal solution parameters. A simulated X-ray powder pattern was prepared from the single crystal data and compared to the experimentally obtained powder pattern and is shown in fig. 14 as a superimposed plot of the X-ray powder diffraction pattern of example 1. Fig. 12 is a superimposed graph of a simulated X-ray powder diffraction pattern and the X-ray powder diffraction pattern obtained from example 2. Fig. 15 is 1: 1R-fasorasitan: simulated X-ray powder diffraction pattern of the PABA co-crystal.

Table 4-R-fasorasitan: crystal data and structural analysis of PABA (1: 1) cocrystal

Example 4 preparation of R-fasoracetam monohydrate form II

Form II R-fasoracetam monohydrate was obtained by adding water to 50.69mg of form I R-fasoracetam monohydrate (available from Aevi Genomic Medicine) until completely dissolved. The solution was then evaporated at room temperature for 21 days, after which a crystalline powder was obtained, which is shown in fig. 16 as R-fasoracetam monohydrate form II. FIG. 17 is a DSC thermogram of R-fasoracetam monohydrate form II.

Example 5 preparation of Anhydrous R-Fasorasitan

Form I R-fasoracetam monohydrate was obtained from commercial, Inc. of Jinnhao Hua, and placed in a round bottom flask and rotary evaporated at 65 ℃ for 30 minutes. Melting was observed and then recrystallized. The X-ray powder diffraction pattern of the resulting dry sample solid is shown as a mixture of R-fasoracetam forms. FIG. 18 shows a superimposed plot of diffraction patterns of a mixture of R-fasorracetam forms, based on a simulated plot of single crystal solutions from components of the R-fasorracetam forms, compared to experimental diffraction patterns of a mixture of R-fasorracetam forms.

To measure the X-ray powder diffraction pattern of anhydrous R-fasorasitan, the mixture was placed at 80 ℃. At this temperature, only the anhydride pattern remained, as shown in fig. 19. FIG. 20 is a DSC thermogram of a mixture of R-fasoracetam monohydrate form I, R-fasoracetam monohydrate form II, and anhydrous R-fasoracetam. The thermogram shows an initial temperature of about 93.5 ℃. DSC showed an additional endothermic initiation event at about 55 ℃, which may be due to the presence of R-fasoracetam monohydrate form I and/or R-fasoracetam monohydrate form II.

Example 6 preparation of R-Fasorasitan-PABA cocrystals with scaling-up of R-Fasorasitan form mixture

A Mettler Easymax system was used with a 100ml reactor, the solution being charged with a temperature probe. 19.63g (0.10mol, 1 eq) of a mixture of form I R-fasoracetam monohydrate (Aevi Genomic Medicine), form II R-fasoracetam monohydrate and anhydrous R-fasoracetam (prepared according to the method of example 11) and 75ml of ethyl acetate were added to the reactor. Agitation was started at 400 rpm. The reactor was heated to 60 ℃. The clear solution was allowed to stand at 60 ℃ for 30 minutes. After cooling the solution to 25 ℃ in 30 minutes. At this stage, all of the fasorasitan remains in solution. Once a temperature of 25 ℃ was reached, 4-aminobenzoic acid (13.72g, 0.10mmol, 1 eq.) was added. The solution was light orange and some of the solid was not dissolved. After 5 minutes, densification of the solid phase occurred. After 30 minutes of adding the 4-aminobenzoic acid, 50.24mg of R-fasoracetam-PABA seed crystals were added. Seed crystals were prepared by the following method: 69.86mg of R-fasoracetam monohydrate form I (supplied by Aevi Genomic Medicine) were milled with 44.97mg of PABA and 3 stainless steel milling beads at a frequency of 30Hz for 90 minutes using Retsch MM 400. After inoculation, the mixture was allowed to stand at 25 ℃ for a further 1 hour. The mixture was then cooled to 10 ℃ with a slope of 0.3 ℃/min. The mixture was allowed to stand at 10 ℃ for 1 hour, then it was filtered and the filtrate was washed twice with 25ml cold EtOAc (3 ℃). The solid was left to dry at room temperature for 48 hours. A mass of 29.84g was recovered, corresponding to a yield of 89%. Fig. 22 is an experimental XRPD pattern of the co-crystal thus obtained, and fig. 23 is a superimposed graph of the experimental pattern and a simulated pattern from single crystal data.

Example 7 preparation of Fasoracetam-PABA cocrystal at Scale-Up Using R-Fasoracetam monohydrate form I

A Mettler Easymax system was used with a 100ml reactor, the solution being charged with a temperature probe. Form I R-fasoracetam monohydrate (Aevi Genomic Medicine) (9.64g, 0.045mol, 1 eq.) and PABA (6.21g, 0.045mol, 1 eq.) and 75ml ethyl acetate were added to the reactor. Agitation was started at 400 rpm. The reactor was heated to 70 ℃. The clear solution was allowed to stand at 70 ℃ for 30 minutes. After cooling the solution to 54 ℃ in 15 minutes. At this stage, all compounds remain in solution. After 5 minutes at 54 ℃, 50.34mg of R-fasoracetam-PABA seed crystals were added. Seed crystals were prepared by the following method: 70.77mg of R-fasoracetam monohydrate form I (supplied by Aevi Genomic Medicine) were milled with 44.98mg of PABA and 3 stainless steel milling beads at a frequency of 30Hz for 90 minutes using Retsch MM 400. After inoculation, the mixture was allowed to stand at 54 ℃ for 2 hours. The mixture was then cooled to 10 ℃ with a slope of 0.3 ℃/min. The mixture was allowed to stand at 10 ℃ for 1 hour, then it was filtered and the filtrate was washed twice with 25ml cold EtOAc (3 ℃). The solid was left to dry at room temperature for 48 hours. A mass of 11.18g was recovered, corresponding to a yield of 74%. Fig. 24 is an experimental XRPD pattern of the co-crystal thus obtained, and fig. 25 is a superimposed graph of the experimental pattern and a simulated pattern from single crystal data.

Example 8 Single Crystal preparation of R-Fasorasiracetam monohydrate form II

Dissolving R-fasoracetam monohydrate type I of the Jinan Hao Hua industry Co., Ltd in methanol. The solution was then allowed to stand at room temperature to evaporate slowly to give a crystalline material. A simulated X-ray powder plot was prepared from the single crystal data solution and compared to the experimentally obtained powder plot of example 4 (fig. 16), as shown in fig. 26. The ORTEP plot can be seen in fig. 27, table 5 is a list of single crystal data parameters. Figure 28 is a simulated XRPD pattern.

TABLE 5 Crystal data and structural analysis of R-Fasorasitan monohydrate form II

Example 9 Single Crystal Anhydrous R-Fasorasitan

The type I R-fasoracetam monohydrate from denham Haohua practice Ltd was placed under vacuum at 60 ℃ and melting was observed. After one week, the temperature was lowered and the vacuum condition was maintained. Crystalline material appeared and was found to be anhydrous R-fasorasitan. The ORTEP plot can be seen in fig. 29, table 6 is a list of single crystal data parameters. Fig. 30 is a simulated XRPD pattern and fig. 31 is an overlay of the simulated pattern and a pattern of anhydrous R-fasoracetam.

Table 6-crystal data and structural analysis of anhydrous R-fasorasitan

Example 10-Single Crystal of R-Fasorasiracetam monohydrate form I

Dissolving R-fasoracetam monohydrate I of the Jinan Hao Hua industry Co., Ltd in water. The solution was then allowed to stand at room temperature and slowly evaporated to give a crystalline material which was analyzed and found to be form I R-fasoracetam monohydrate. The ORTEP plot can be seen in fig. 32, table 7 is a list of single crystal data parameters. FIG. 33 is a simulated XRPD pattern and FIG. 34 is a superposition of the simulated pattern and a pattern of R-fasoracetam monohydrate form I, indicating a match.

TABLE 7 Crystal data and structural analysis of form I R-Fasorasitan monohydrate

Example 11 mixture of forms of R-Fasorasiracetam

Type I R-fasorexiptan monohydrate from dennhua industries ltd was placed in a round bottom flask and placed in vacuum in a rotary evaporator apparatus at 65 ℃. Melting of form I R-fasoracetam monohydrate was observed. The sample was placed under vacuum in a rotary evaporator at 65 ℃ for 30 minutes during which time recrystallization occurred. The sample was then left to recrystallize completely. FIG. 18 shows an X-ray powder diffraction pattern of the resulting sample compared to simulated X-ray powder diffraction patterns of simulated patterns corresponding to each of R-fasoracetam monohydrate form I, R-fasoracetam monohydrate form II, and anhydrous R-fasoracetam.

Example 12 Single crystal Co-crystals of Fasorasiracetam and Urea (1: 1) (type B)

1 of R-fasorasitan and urea was obtained as follows: 1 stoichiometric eutectic. 201.28mg of form I R-fasoracetam monohydrate from Aevi Genomic Medicine was placed in vacuo for 50 minutes in a rotary evaporator at 65 ℃. The sample was cooled to room temperature and 55.1mg of urea was added. The mixture was then held at 120 ℃ for 10 minutes until completely melted. The temperature was then left at 90 ℃ for 24 hours, after which R-fasorasitan was obtained: single crystals of urea eutectic. FIG. 36 is an ORTEP plot of a single crystal solution of a co-crystal of R-fasorracetam and urea. Table 7A lists the single crystal parameters of the co-crystals of R-fasorasitan and urea. FIG. 37 is a simulated X-ray powder diffraction pattern of a single crystal solution from a co-crystal of R-fasorracetam and urea.

Table 7 1 of a-R-fasorasitan and urea: 1 single crystal parameter of the eutectic.

Example 13 Co-crystals of Fasorasiracetam and Urea (type B)

6.49mg of urea and 20.19mg (1: 1 molar ratio) of the mixture of R-fasoracetam forms prepared according to example 16 were added to Eppendorf together with 3 stainless steel grinding beads and 10. mu.L of toluene. The mixture was milled in a RETSCH Mixer Mill MM 400 for 90 minutes at a beating frequency of 30Hz to give a milled crystalline material showing the presence of a co-crystal of R-fasoracetam and urea. FIG. 38 is a superimposed plot of x-ray powder diffraction patterns showing a co-crystal of R-fasorracetam and urea from this example 13, compared to R-fasorracetam of FIG. 37: simulation diagram of urea eutectic. FIG. 39 is an XRPD overlay showing a co-crystal of R-fasoracetam and urea, compared to R-fasoracetam: urea eutectic, a type I R-fasoracetam monohydrate, a type II R-fasoracetam monohydrate, and an anhydrous R-fasoracetam simulation diagram. FIG. 40 is a differential scanning calorimetry thermogram of a co-crystal of fasorracetam and urea prepared in this example, showing a single endotherm with an onset temperature of about 102 ℃.

Example 14 Co-crystals of Fasorasiracetam and Urea (type B)

141.5mg urea and 502.3mg (molar ratio 1: 1) R-fasoracetam monohydrate form I (available from Aevi Genomic Medicine) were placed under vacuum in a rotary evaporator at 65 ℃ for 1 hour, during which time crystallization occurred. The sample was then cooled to room temperature. FIG. 41 is a superimposed plot of X-ray powder diffraction patterns showing a co-crystal of R-fasoracetam and urea, compared to R-fasoracetam: simulation diagram of urea eutectic. FIG. 42 is an XRPD overlay showing a co-crystal of R-fasoracetam and urea compared to R-fasoracetam: urea eutectic, a type I R-fasoracetam monohydrate, a type II R-fasoracetam monohydrate, and an anhydrous R-fasoracetam simulation diagram.

Example 15 Co-crystals of R-fasorasitan and Urea (type A)

6.32mg of urea and 19.75mg (1: 1 molar ratio) of the mixture of forms of R-fasoracetam prepared according to example 11 and/or example 16 were added to Eppendorf together with 3 stainless steel grinding beads. The mixture was milled in a RETSCH Mixer Mill MM 400 for 90 minutes at a beating frequency of 30Hz to give a milled crystalline material showing the presence of a co-crystal of R-fasoracetam and urea. FIG. 35 is a superimposed graph of X-ray powder diffraction patterns showing a co-crystal of R-fasoracetam and urea compared to a mixture of urea and R-fasoracetam forms. FIG. 43 is an XRPD overlay showing a co-crystal of R-fasorracetam and urea, compared to urea and form I. FIG. 44 is a selected peak X-ray powder diffraction pattern of a co-crystal of R-fasorasitan and urea. FIG. 113 is an X-ray powder diffraction pattern of urea. FIG. 46 shows a state of a solution of a dissolved eutectic of R-fasorracetam and urea ¹H-NMR spectrum, showing that all hydrogen was taken in and not degraded. FIG. 47 is a differential scanning calorimetry thermogram of a co-crystal of R-fasorracetam and urea showing a single endotherm with a shoulder, and FIG. 48 is a differential scanning calorimetry thermogram of urea. However, the DSC thermogram of the co-crystal shows an onset temperature of about 103 ℃, i.e. the onset temperature of form B, indicating that the material has transformed to form B at the completion of the DSC measurement. FIG. 49 is an XRPD overlay comparing the XPRD pattern of the co-crystal of example 15 with a simulated XRPD pattern of the single crystal of example 12.

Example 16 Fasorasiracetam Format mixture

A mixture of R-fasoracetam monohydrate form I, R-fasoracetam monohydrate form II, and anhydrous R-fasoracetam was prepared by placing R-fasoracetam monohydrate form I, purchased from Funanhao Hua industries, Inc., in a vacuum rotary evaporator at 65 deg.C. When the compound begins to melt, water is removed from the melt. After about 30 minutes, the mixture cured.

Example 17 eutectic of R-Fasorasitan and trimesic acid

The co-crystal of R-fasoracetam and trimesic acid was prepared by the following method: 32.23mg of trimesic acid and 30.25mg of R-fasoracetam monohydrate form I (molar ratio 1: 1) were added to Eppendorf together with 3 stainless steel grinding beads. The mixture was milled in a RETSCH Mixer Mill MM 400 for 90 minutes at a beating frequency of 30Hz to give a milled crystalline material. FIG. 50 is a superimposed plot of the X-ray powder diffraction pattern of the milled crystalline material compared to the plots of trimellitic acid and R-fasoracetam monohydrate form I, indicating a co-crystal of R-fasoracetam and trimesic acid. FIG. 51 is an X-ray powder diffraction pattern of a cocrystal of R-valiracetam and trimesic acid, and FIG. 52 is an X-ray powder diffraction pattern of trimesic acid. FIG. 53 shows a dissolved cocrystal of R-fasoracetam and trimesic acid ¹H-NMR spectrum, all hydrogen is taken in, with no sign of degradation. FIG. 54 is a differential scanning calorimetry thermogram of a co-crystal of R-fasoracetam and trimesic acid showing a single endothermic peak, and FIG. 55 is a differential scanning calorimetry thermogram of trimesic acid.

Example 18 Single Crystal Co-crystals of Fasorexiptan and R-ibuprofen

1 of R-fasoracetam and R-ibuprofen can be prepared by slow evaporation of equimolar ratios of R-fasoracetam monohydrate and RS-ibuprofen form I in EtOH: 1 stoichiometric eutectic. During evaporation, the solution can be seeded with seed crystals of the product of example 19. FIG. 56 is an ORTEP plot of a single crystal solution of a co-crystal of R-fasorasitan and R-ibuprofen. Table 8 lists the single crystal parameters of the co-crystals of R-fasorasitan and R-ibuprofen. FIG. 57 is a simulated X-ray powder diffraction pattern of a single crystal solution from a co-crystal of R-fasorasitan and R-ibuprofen.

Table 8-1 of R-fasorasitan and R-ibuprofen: 1 single crystal parameter of the eutectic.

Example 19-milled crystalline R-Fasorasiracetam and R-ibuprofen

Milled crystalline R-fasoracetam and R-ibuprofen were prepared by the following method: 25.3mg ibuprofen and 27.9mg R-fasoracetam monohydrate form I (available from denna haohua industries ltd.) were added to Eppendorf together with 3 stainless steel grinding beads. The mixture was milled in a RETSCH Mixer Mill MM 400 at a beating frequency of 30Hz for 90 minutes to produce a milled crystalline material of R-fasoracetam and R-ibuprofen to produce milled crystalline R-fasoracetam R-ibuprofen. FIG. 58 is an X-ray powder diffraction pattern of milled crystalline R-fasoracetam and R-ibuprofen materials. Figure 59 is an XRPD pattern of R-ibuprofen. FIG. 60 is a superimposed plot of an XRPD pattern of a milled crystalline R-fasoracetam R-ibuprofen material compared to a simulated XRPD pattern of FIG. 57. FIG. 61 is a DSC thermogram of milled crystalline R-fasoracetam R-ibuprofen material and FIG. 62 is a DSC thermogram of R-ibuprofen.

Example 20 Single crystal Co-crystals of Fasorasiracetam and phthalic acid (1: 1)

1 of R-fasorasitan and phthalic acid was obtained by the following method: 1 single crystal of eutectic: stoichiometric amounts of R-fasorasitan (30mg of form I R-fasorasitan monohydrate) and phthalic acid were dissolved in EtOH, and then the ethanol was slowly evaporated to produce a eutectic single crystal. Single crystal data for this co-crystal is provided in table 9, and figure 63 is an ORTEP plot of single crystal data. FIG. 64 is a simulated X-ray powder diffraction pattern of a co-crystal of R-fasoracetam and phthalic acid obtained from single crystal data collected on a single crystal. FIG. 65 is an X-ray powder diffraction pattern of phthalic acid.

Table 9-1 of R-fasorasitan and phthalic acid: 1 single crystal solution parameters of eutectic

Example 21 monohydrate Co-crystals of R-Fasorasitan and phloroglucinol

The monohydrate co-crystal of R-fasorasitan and phloroglucinol is prepared by the following method: 25.7mg of phloroglucinol and 40mg of R-fasoracetam monohydrate form I (available from Jinan Hao Hua industries, Ltd.) were added to Eppendorf together with 3 stainless steel grinding beads. The mixture was milled in a RETSCH Mixer Mill MM 400 at a beating frequency of 30Hz for 90 minutes to form a milled crystalline material which was 1: 1 monohydrate of the co-crystal. FIG. 66 is an X-ray powder diffraction pattern of a monohydrate co-crystal of R-fasoracetam and phloroglucinol. FIG. 67 is an X-ray powder diffraction pattern of phloroglucinol. FIG. 68 is a superimposed X-ray powder diffraction pattern of a co-crystal of R-fasoracetam and phloroglucinol monohydrate, phloroglucinol, and R-fasoracetam monohydrate form I. FIG. 69 is a differential scanning calorimetry thermogram of a monohydrate co-crystal of R-fasorasitan and phloroglucinol, and FIG. 70 is a differential scanning calorimetry thermogram of phloroglucinol.

Example 22 monohydrate Co-crystals of R-Fasorasitan and phloroglucinol

By dissolving stoichiometric amounts of form I R-fasoracetam monohydrate (available from jinan haohua, ltd.) and pyrogallol in EtOH and by slow solvent evaporation, 1: 1: 1 eutectic crystal. Table 10 provides single crystal data for the co-crystals and fig. 71 is an ORTEP plot of the single crystal data. FIG. 72 is a simulated X-ray powder diffraction pattern of a co-crystal of R-fasoracetam and pyrogallol obtained from single crystal data collected on a single crystal. Fig. 73 is a superimposed plot of the experimental plot from example 21 and a simulated plot of the single crystal from this example 22, which match, thus indicating that the milled crystalline material of example 21 is a 1: 1: 1 eutectic crystal.

TABLE 10 Single Crystal data parameters for monohydrate Co-crystals of R-Fasorasitan and phloroglucinol

Example 23-Single Crystal of monohydrate of R-Fasorasitanylmethyl-3, 4, 5-Trihydroxybenzoate

Single crystals of the monohydrate of R-fasoracetam and co-crystal of methyl-3, 4, 5-trihydroxybenzoic acid were prepared by dissolving stoichiometric amounts of 30mg of R-fasoracetam monohydrate (available from jinan hao hua industries ltd.) and methyl-3, 4, 5-trihydroxybenzoate in EtOH and by slow solvent evaporation. Table 11 is data from a single crystal solution of the eutectic, and figure 74 is an ORTEP plot of the single crystal. FIG. 75 is a simulated X-ray powder diffraction pattern of a monohydrate co-crystal of R-fasorasitan and methyl-3, 4, 5-trihydroxybenzoate. FIG. 76 is a superimposed plot of an X-ray powder diffraction pattern of a single crystal of monohydrate R-fasoracetam methyl-3, 4, 5-trihydroxybenzoate and an X-ray powder diffraction pattern of milled crystalline R-fasoracetam and methyl-3, 4, 5-trihydroxybenzoate materials. FIG. 77 is an X-ray powder diffraction pattern of methyl-3, 4, 5-trihydroxybenzoate.

TABLE 11 Single Crystal data parameters for monohydrate of-R-Fasorasitanylmethyl-3, 4, 5-Trihydroxybenzoate

Example 24-1 of R-fasorasitan with ethyl gallate: 1 single crystal of eutectic crystal

By adding a saturated solution of form I R-fasoracetam monohydrate in ethanol to a saturated solution of ethyl gallate in EtOH, a 1: 1 single crystal R-fasorasitan: and 4, ethyl gallate. Equal volumes of the two saturated solutions were added together and the resulting solution was evaporated to give a co-crystal. Table 12 contains single crystal solution data parameters and figure 78 is an ORTEP plot for single crystals. Fig. 79 is a simulated XRPD pattern of the co-crystal.

Table 12-1 of R-fasorasitan and ethyl gallate: 1 single crystal data parameter of eutectic

Example 25-Co-crystals of R-Fasorasiracetam and Ethyl gallate (1: 1)

Milled crystalline R-fasoracetam and ethyl gallate were prepared by the following method: 20.81mg of ethyl gallate and 19.90mg of the material from example 26 were added to Eppendorf together with 3 stainless steel grinding beads. The resulting blend was milled in a RETSCH Mixer Mill MM 400 at a beating frequency of 30Hz for 90 minutes to form a milled crystalline material which was 1: 1 eutectic crystal. Fig. 80 is an XRPD pattern of the milled crystalline material, and fig. 81 is an overlay of the XRPD pattern and a simulated pattern made from a single crystal, showing a match. Figure 82 is an XRPD pattern of ethyl gallate. Fig. 83 is a DSC thermogram of a co-crystal of R-fasoracetam and ethyl gallate prepared according to this example 25, and fig. 84 is a DSC thermogram of ethyl gallate.

Example 26 preparation of a mixture of R-Fasorasiracetam forms

The form I R-fasoracetam monohydrate was placed under vacuum at 65 ℃ by rotary evaporator. The sample began to melt and then water was removed from the melt by rotary evaporation. After about 30 minutes, a mixture of R-fasoracetam forms was obtained.

Example 27-1 of R-fasorasitan with ethyl gallate: 2 single crystal of eutectic crystal

1 of R-fasorasitan and ethyl gallate can be prepared by the following method: 2, eutectic crystal: stoichiometric amounts of the two components were dissolved in ethyl acetate and evaporated through slow solvent, followed by a heat-cool cycle. Table 13 identifies data parameters for single crystal solutions from the eutectic, and figure 85 is an ORTEP plot obtained from the single crystal. FIG. 86 is a simulated XRPD pattern for a single crystal.

Table 13-1 of R-fasorasitan and ethyl gallate: 2 single crystal data parameter of eutectic

Example 28-1 of R-fasorasitan with ethyl gallate: 2 single crystal of dihydrate of eutectic crystal

1, preparing R-fasorasitan and ethyl gallate: 2 a single crystal of a dihydrate of the eutectic. Adding a saturated solution of the type I R-fasoracetam monohydrate in ethyl acetate into a saturated solution of ethyl gallate in ethyl acetate to obtain the single crystal. Equal volumes of the two saturated solutions were added together and the resulting solution was evaporated to give a co-crystal. Table 14 has data parameters for single crystals and fig. 87 is an ORTEP plot for single crystal solutions. FIG. 88 is a simulated XRPD pattern for a single crystal.

Table 14-1 of R-fasorasitan and ethyl gallate: 2 single crystal data parameters of dihydrate of eutectic

Example 29-1 of R-fasorasitan with ethyl gallate: 2 crystalline dihydrate of eutectic crystal

1 of R-fasorasitan and ethyl gallate was prepared by the following method: 2 crystalline dihydrate of cocrystal: 931.8mg of ethyl gallate (2 equivalents) and 505.00mg of R-fasoracetam monohydrate form I (from commercial Inc. of Jinhan Hao Hua) were slurried in 5ml of water under magnetic stirring at room temperature and overnight. After stirring, the sample was filtered and the solid was dried to give 1: 2 crystalline dihydrate of the eutectic. Fig. 89 is an XRPD pattern of the crystalline material thus obtained. FIG. 90 is a simulated XRPD pattern of a dihydrate mono-co-crystal of 1: 2R-fasorasitan and ethyl gallate, superimposed with the crystalline material of example 29, showing matching. Thus, the crystalline material of this example 29 was a dihydrate of a co-crystal of R-fasoracetam and ethyl gallate (1: 2). FIG. 91 is a cycle DSC thermogram of a dihydrate of a co-crystal of R-fasorasitan and ethyl gallate (1: 2), and FIG. 92 is a DSC thermogram of a dihydrate of a co-crystal of R-fasorasitan and ethyl gallate.

Example 30-milled crystalline R-Fasorasiracetam and 6-hydroxy-2-naphthoic acid

Milled crystalline R-fasorasitan and 6-hydroxy-2-naphthoic acid were prepared by the following method: 28.88mg of 6-hydroxy-2-naphthoic acid and 30.26mg of R-fasoracetam monohydrate form I (available from Jinan Hao Hua Engineers, Inc.) were added to Eppendorf together with 3 stainless steel grinding beads to form a mixture. The mixture was milled in a RETSCH Mixer Mill MM 400 at a beating frequency of 30Hz for 90 minutes to provide R-fasoracetam and 6-hydroxy-2-naphthoic acidThe milled crystalline material of (a). FIG. 93 is an XRPD pattern for milled crystalline R-fasoracetam and 6-hydroxy-2-naphthoic acid material. FIG. 94 is an XRPD pattern for 6-hydroxy-2-naphthoic acid, and FIG. 95 is a superimposed plot of the XRPD patterns for R-fasoracetam monohydrate form I, milled crystalline R-fasoracetam and 6-hydroxy-2-naphthoic acid material, and 6-hydroxy-2-naphthoic acid. This preparation was repeated using 38.36mg of 6-hydroxy-2-naphthoic acid and 40mg of R-fasoracetam monohydrate form I. FIG. 96 is a drawing of a solution of milled crystalline R-fasorasitan and 6-hydroxy-2-naphthoic acid¹H-NMR spectrum, in which all hydrogen was taken in, and no degradation was observed. FIG. 97 is a DSC thermogram of milled crystalline soraferacetam and 6-hydroxy-2-naphthoic acid with a single endothermic peak observed, and FIG. 98 is a DSC thermogram of 6-hydroxy-2-naphthoic acid. According to the data provided, and since the XRPD pattern of the milled crystalline material is different from the XRPD pattern of the components in the mixture, the milled crystalline material is a co-crystal of R-fasoracetam with 6-hydroxy-2-naphthoic acid.

Example 31 Single Crystal of R-Fasorasiracetam and 4-Nitrobenzoic acid (1: 2)

By dissolving stoichiometric amounts of form I R-fasoracetam monohydrate (available from denna hai wawa ltd.) and 4-nitrobenzoic acid in EtOH, and by slow solvent evaporation, 1: 2R-fasoracetam was obtained: 4-nitrobenzoic acid eutectic. Table 15 lists the parameters of the single crystal X-ray solution and figure 99 is an ORTEP plot of the co-crystals. Fig. 100 is a simulated XRPD pattern of the co-crystal of example 31.

TABLE 15 Single Crystal data parameters

Example 32-milled crystalline R-Fasorasitan and 4-nitrobenzoic acid

Milled crystalline R-fasoracetam and 4-nitrobenzoic acid were prepared by the following method: 34.06mg of 4-nitrobenzoic acid (2 equivalents) and 20.00mg of R-fasoracetam monohydrate form I (1 equivalent) (available from Jinhan Hao Hua Kogyo Co., Ltd.) were added to Eppendorf together with 3 stainless steel grinding beads to form a mixture. The mixture was milled in a RETSCH Mixer Mill MM 400 at a beating frequency of 30Hz for 90 minutes to form a crystalline milled material of R-fasoracetam and 4-nitrobenzoic acid. Figure 101 is an XRPD pattern of milled crystalline material. FIG. 102 is an XRPD pattern for 4-nitrobenzoic acid. FIG. 103 is a superimposed plot of the XRPD pattern of the milled crystalline material versus 4-nitrobenzoic acid and R-fasoracetam monohydrate form I. Fig. 104 is an XRPD overlay of a simulated XRPD pattern of the co-crystal and an XRPD pattern of the milled crystalline material, matched. Thus, the crystalline material being milled is a 1:2 eutectic crystal. FIG. 105 is a DSC thermogram of the milled crystalline material and FIG. 106 is a DSC of 4-nitrobenzoic acid.

Example 33-milled crystalline R-fasorasitan and 2-indole-3-acetic acid

Milled crystalline R-fasoracetam and 2-indole-3-acetic acid material was prepared by adding 17.98mg of 2-indole-3-acetic acid and 21.33mg of the material of example 26 to Eppendorf together with 3 stainless steel grinding beads and 10. mu.l of toluene to form a mixture. The mixture was milled in a RETSCH Mixer Mill MM 400 for 90 minutes at a beating frequency of 30Hz to give a milled crystalline material. Figure 107 is an XRPD pattern of milled crystalline material. FIG. 108 is an XRPD pattern for 2-indole-3-acetic acid. FIG. 109 is a superimposed plot of the XRPD patterns of milled crystalline, 2-indole-3-acetic acid and form I R-fasoracetam monohydrate material. FIG. 110 is a drawing of a solution of milled crystalline material¹H-NMR spectrum, and all hydrogen taken into account, showed no degradation. FIG. 111 is a DSC thermogram of milled crystalline material. FIG. 112 is a DSC thermogram of 2-indole-3-acetic acid.

Example 34-form B R-fasorasiracetam: the urea eutectic is prepared in a scale-up manner.

13g of R-fasoracetam monohydrate form I (available from Aevi Genomic Medicine) was added to a 100ml reactor vessel of a Mettler Toledo Easymax system equipped with an overhead stirrer. 50ml of ethyl acetate are added and the suspension is heated to 60 ℃. Dissolution occurs upon heating. After 10 minutes at 60 ℃, 3.46g urea (0.95 eq) was added to the solution and the suspension was left to stand for 2 h. The suspension was then cooled to-10 ℃ at a cooling rate of 0.3 ℃/min and left at this temperature for 1.5 h. After filtration, the filter cake was washed with 10ml of ethyl acetate maintained at 9 ℃. The solid was dried at room temperature. A mass of 14.12g was recovered, corresponding to a yield of 91% relative to the amount of R-fasoracetam bound. FIG. 116 shows the R-fasoracetam form B so prepared: DSC thermogram of urea co-crystal, fig. 117 is XRPD pattern of recovered powder with R-fasoracetam form B: overlay of simulated views of urea co-crystals.

Example 35-form B R-fasorasiracetam: estimation of solubility of urea co-crystals

At room temperature, 5g of R-fasorasitan form B prepared in example 34: the urea co-crystal was added to 1ml of water in a round bottom flask. Complete dissolution did not occur. The suspension was left under magnetic stirring for 15 minutes. 200 μ l of water was added and held for an additional 15 minutes. No dissolution occurred. An additional 200. mu.l of water was added and held for an additional 15 minutes. No dissolution occurred. 200 μ l of water was added and held for an additional 15 minutes. No dissolution occurred. 200 μ l of water was added and held for an additional 15 minutes. Complete dissolution occurred. Thus, 5g of R-fasorasitan form B was dissolved: the urea co-crystal requires a total of 1.8ml of water.

Example 36-form a R-fasorasiracetam: and (4) synthesizing urea eutectic.

25.03g of R-fasoracetam monohydrate form I and 116mL of ethyl acetate are combined and hot fine filtered (polish filtered hot) and maintained at 60 ℃. 6.62g of a product from M were added&P milled urea (0.94 eq). The solid dissolved to form a two-phase mixture which was held at 60 ℃ for two hours and then cooled at 18 ℃ per hour and the oil was observed to solidify at 23 ℃ at the bottom of the reactor. The reactor was heated to 43 ℃ and the oil was reformed. The mixture was then seeded with 128mg of the material of example 37 and held at 43 ℃ for 1.5 hours. The mixture was then cooled to 9 ℃ at 18 ℃ per hour and held overnight. The obtained suspension was filtered And washed with 17mL of cold ethyl acetate. The wet cake was then oven dried at 43 ℃ for 22 hours under vacuum to yield 26.47 g of form a co-crystal. By passing through the solution state¹H and¹³the chemical composition was confirmed by C NMR. Form a was confirmed by XRPD (figure 118) and DSC (figure 119). A list of peaks corresponding to fig. 118 is shown in table 16 below.

TABLE 16-Peak Table of FIG. 118

2θ	2θ	2θ
			10.4	20.9	30.7
10.8	21.6	31.1
			12.2	22.2	31.6
13.2	22.8	32.5
			14.1	23.8	33.0
15.2	24.6	33.6
			16.1	25.1	34.0
17.4	26.7	34.6
			18.3	27.2
18.9	27.9
			19.2	28.6
19.9	29.3

EXAMPLE 37 preparation of the seed crystals of example 36

100 grams of D-pyroglutamic acid (available from Wilshire) was reacted with 0.91 equivalents of piperidine in ethyl acetate to produce a solution of R-fasoracetam in ethyl acetate. An aliquot of the solution was brought to 5 relative volumes with ethyl acetate (161 grams of solution in total) and hot fine filtered and cooled to 43 ℃. 14.1 g of urea were added to the solution and after 1 hour the suspension was heated to reflux. A three-phase mixture was formed and the mixture was cooled to 20 ℃ at a rate of 20 ℃ per hour and held overnight. The resulting suspension was filtered and washed with 50mL ethyl acetate. The wet cake was dried in a vacuum oven at 40 ℃ for 70 hours to give 47.0 g. A portion of the resulting solid was used as seed in example 36.

Example 38 stability of R-Fasoracetam cocrystals type A

Opening a batch containing R-fasorasiracetam form a prepared according to example 36: vials of urea co-crystals were obtained and analyzed by XRPD (fig. 120) and DSC (fig. 121-showing two large endotherms). XRPD showed the presence of predominantly form a and some form B, as illustrated by the peak at 11.4 ° 2 θ. The vial was then closed and placed at-15 ℃. Daily, the material in the sample vial was sampled and analyzed by XRPD. In parallel, a sample of this compound was left open at room temperature and the same sample was analyzed by XRPD every day. In room temperature experiments, as can be seen by XRPD, figure 122 shows R-fasorasiracetam form a: the urea co-crystal is completely converted into form B within two days. As shown in FIG. 123, the sample also converted to form B at-15 ℃. Thus, form a proved to be R-fasorasiracetam compared to the more stable form B: metastable polymorphs of urea co-crystals.

The DSC thermogram of FIG. 121 (above) was performed at a rate of 20 deg.C/min. In fig. 121, form a begins to melt at about 91 c, then recrystallizes to form B, and subsequently form B begins to melt at about 104 c. These data confirm that form a is a metastable crystal form and recrystallizes to the more stable form B upon melting.

Example 39-R-fasorasiracetam: preparation of seed crystals of PABA co-crystal

By dividing 1: 1 proportion of the type I R-fasoracetam monohydrate and 4-aminobenzoic acid are slurried in 20mL ethyl acetate for 4 days to obtain eutectic crystal seeds. After 4 days, the slurry was filtered and washed 2 times with 20mL of cold (-15 ℃ C.) ethyl acetate. By XRPD and¹H-NMR spectrum confirmsThe presence of a co-crystal.

Example 40-R-fasorasiracetam: scaling up of the PABA eutectic (FIG. 136)

The R-fasoracetam form mixture (20.07g, 0.10mol) was dissolved in ethyl acetate (75 mL). The suspension was stirred at 150RPM and heated from room temperature to 60 ℃ at a heating rate of 5 ° per minute. To ensure complete dissolution (although complete dissolution was observed at 54 ℃), the solution was left at 60 ℃ for 30 minutes. After isothermal hold, cool to 25 ℃ at a cooling rate of 5 ° per minute, followed by addition of 1 equivalent of 4-aminobenzoic acid (13.86g, 0.10 mol). 5 minutes after the addition of the co-crystal former, a white paste appeared and the suspension formed thickened. The paste was analyzed by XRPD and confirmed to be a co-crystal. After the suspension was held at 25 ℃ for 1 hour, it was seeded with 5 wt% of the co-crystal from example 39 (1.69g) and allowed to stand for an additional 1 hour to ensure that the only solid formed was the desired co-crystal. Finally, the suspension was cooled to 10 ℃, filtered, and washed twice by displacement with cold ethyl acetate (30mL, 10 ℃), wherein the presence of the co-crystal only was confirmed by XRPD analysis. The yield recorded for this procedure was 86%. The crystallization process in this example was completed using a 500mL Double J Reactor apparatus from Cambridge Reactor Design.

EXAMPLE 41 preparation of the phase diagrams of FIG. 137

Different vials were prepared with different masses of R-fasorasitan form mixture, PABA and ethyl acetate. A magnet was placed in each vial, the vial was closed and left at room temperature for one hour. After one hour of holding, each vial was inoculated with R-fasorasitan: eutectic seed crystals of PABA (prepared by milling about 70.01mg of R-fasoracetam monohydrate form I and about 44.95mg of PABA at 30Hz for 90 minutes). Vials were also inoculated with R-fasoracetam form mixture and PABA. The sample was then left at room temperature for an additional 48 hours under magnetic stirring. Thereafter, the liquid phase was analyzed using HPLC and the solid phase (obtained after filtration) was analyzed using XRPD. The data is plotted in the ternary phase diagram of fig. 137, and the lines in fig. 137 are plotted based on the data as a guide.

Example 42 Co-crystals of Fasorasiracetam and Urea (type B) scaling-Up

1500.6g of R-fasoracetam monohydrate form I were charged into a vessel with 5.26 liters of ethyl acetate (water content about 0.01%) and heated to about 40 ℃ to form an orange-brown solution. The solution was fine filtered through a 1 micron filter and the filtrate was vacuum transferred to the reactor. The filtrate was combined with 0.60L of warm ethyl acetate (as a rinse) into a single reactor and heated to about 50 ℃ and the solution was stirred. 204 g of urea (0.485 eq) were added to the reactor. After about half an hour, 204.2 grams of urea (0.486 eq) was added and held for 15 minutes. 74.8 grams of the previously prepared seed crystals of form B were added to a reactor maintained at a temperature of 51 deg.C to 52 deg.C for about 2 hours, then cooled to about-14 deg.C over 14 hours, and maintained at about-10 deg.C for 6 hours. The solid was isolated by filtration and washed with ethyl acetate. After vacuum oven drying, form B was prepared with an orange hue and a mass of 1749.8 grams. Form B was confirmed by DSC and XRPD. It is believed that the orange hue is due to small amounts of impurities. No impurities were detected by XRPD, confirmed as form B.

Claims (371)

1. A co-crystal of fasoracetam and a co-crystal former, wherein the co-crystal former is not tartaric acid.

2. The co-crystal of claim 1, wherein the co-crystal former is an organic compound and comprises at least one selected from-NH₂、-NO₂Alkyl, or a moiety containing a carbonyl moiety.

3. The co-crystal of claim 1 or 2, wherein the fasorasitan is R-fasorasitan.

4. A crystalline compound comprising fasorasiracetam and a co-crystal former, wherein the co-crystal former is an aromatic compound.

5. A crystalline compound comprising R-fasorasitan and a co-crystal former, wherein the co-crystal former is an aromatic compound.

6. The crystalline compound according to claim 4 or 5, wherein the crystalline compound is a co-crystal.

7. A co-crystal of fasorasitan and a co-crystal former, wherein the co-crystal former is an aromatic compound.

A co-crystal of R-fasorasitan and a co-crystal former, wherein the co-crystal former is an aromatic compound.

9. The co-crystal of claim 7 or 8, wherein the aromatic compound has at least one substituent.

10. The co-crystal of claim 9, wherein the at least one substituent is selected from-OH, -NH ₂Alkyl, -NO₂And a carbonyl-containing moiety.

11. The co-crystal of claim 10, wherein the carbonyl-containing moiety is an organic acid moiety.

12. The co-crystal of claim 11, wherein the organic acid moiety is selected from C₁-C₄An organic acid.

13. The co-crystal of claim 12, wherein the organic acid moiety is-COOH.

14. The co-crystal of claim 10, wherein the at least one substituent is an-OH moiety.

15. The co-crystal of claim 10, wherein the at least one substituent is selected from an ester and an alkyl moiety.

16. The co-crystal of claim 15, wherein the ester is selected from C₁-C₅And (3) an ester.

17. The co-crystal of any one of claims 9-16, wherein the aromatic compound has two substituents.

18. The co-crystal of any one of claims 9-16, wherein the aromatic compound has three substituents.

19. The co-crystal of any one of claims 9-16, wherein the aromatic compound has four substituents.

20. The co-crystal of claim 17, wherein there are two substituents, and each substituent is independently selected from-OH, -NH₂Alkyl, organic acids, esters and-NO ₂And (4) partial.

21. The co-crystal of claim 20, wherein the first substituent is an organic acid and the second substituent is selected from the group consisting of-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial.

22. The co-crystal of claim 21, wherein the second substituent is-NH₂And (4) partial.

23. The co-crystal of claim 22, wherein the-NH₂Moieties and the organic acid moieties are ortho to each other.

24. The co-crystal of claim 22, wherein the-NH₂Moieties and the organic acid moiety are meta to each other.

25. The co-crystal of claim 22, wherein the-NH₂Moieties and the organic acid moiety are para to each other.

26. The co-crystal of claim 21, wherein the second substitutionRadical is-NO₂And (4) partial.

27. The co-crystal of claim 26, wherein the-NO₂Moieties and the organic acid moieties are ortho to each other.

28. The co-crystal of claim 26, wherein the-NO₂Moieties and the organic acid moiety are meta to each other.

29. The co-crystal of claim 26, wherein the-NO₂Moieties and the organic acid moiety are para to each other.

30. The co-crystal of claim 21, wherein the second substituent is an-OH moiety.

31. The co-crystal of claim 30, wherein the-OH moiety and the organic acid moiety are ortho to each other.

32. The co-crystal of claim 30, wherein the-OH moiety and the organic acid moiety are meta to each other.

33. The co-crystal of claim 30, wherein the-OH moiety and the organic acid moiety are para to each other.

34. The co-crystal of claim 21, wherein the second substituent is an alkyl moiety.

35. The co-crystal of claim 34, wherein the alkyl moiety and the organic acid moiety are ortho to each other.

36. The co-crystal of claim 34, wherein the alkyl moiety and the organic acid moiety are meta to each other.

37. The co-crystal of claim 34, wherein the alkyl moiety and the organic acid moiety are para to each other.

38. The co-crystal of claim 21, wherein the second substituent is an organic acid moiety.

39. The co-crystal of claim 38, wherein two organic acid moieties are ortho to each other.

40. The co-crystal of claim 38, wherein the two organic acid moieties are meta to each other.

41. The co-crystal of claim 38, wherein two organic acid moieties are para to each other.

42. The co-crystal of claim 21, wherein the second substituent is an ester moiety.

43. The co-crystal of claim 42, wherein the ester moiety and the organic acid moiety are ortho to each other.

44. The co-crystal of claim 42, wherein the ester moiety and the organic acid moiety are meta to each other.

45. The co-crystal of claim 42, wherein the ester moiety and the organic acid moiety are para to each other.

46. The co-crystal of claim 18, wherein there are three substituents, and each substituent is independently selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial.

47. The co-crystal of claim 46, wherein the first substituent is-OH.

48. The co-crystal of claim 47, wherein the second substituent and the third substituent are-OH.

49. The co-crystal of claim 46, wherein the first substituent is an organic acid moiety.

50. The co-crystal of claim 49, wherein the second substituent and the third substituent are organic acid moieties.

51. The co-crystal of any one of claims 49-50, wherein the organic acid moiety is-COOH.

52. The co-crystal of claim 19, wherein there are four substituents, and each substituent is independently selected from-OH, -NH ₂Alkyl, organic acids, esters and-NO₂And (4) partial.

53. The co-crystal of claim 52, wherein the first substituent is an ester moiety or an organic acid moiety.

54. The co-crystal of claim 53, wherein the ester is a methyl ester.

55. The co-crystal of claim 53, wherein the ester is an ethyl ester.

56. The co-crystal of any one of claims 53-55, wherein the second substituent is an-OH moiety.

57. The co-crystal of any one of claims 53-55, wherein the second substituent, the third substituent, and the fourth substituent are each an-OH moiety.

58. The co-crystal of any one of claims 7-22, wherein the aromatic compound is polycyclic.

59. The co-crystal of any one of claims 26, 30, 34, 42, 46, and 49-57, wherein the aromatic compound is polycyclic.

60. The co-crystal of any one of claims 58-59, wherein the polycyclic aromatic compound is two six-membered rings.

61. The co-crystal of any one of claims 58-59, wherein the polycyclic aromatic compound is one six-membered ring and one five-membered ring.

62. The co-crystal of any one of claims 7-61, wherein the ring atoms of the aromatic compound are all carbon.

63. The co-crystal of any one of claims 7-61, wherein at least one ring atom of the aromatic compound is not carbon.

64. The co-crystal of claim 63, wherein at least one ring atom is nitrogen.

65. The co-crystal of any one of claims 58-59, wherein there is one substituent on the polycyclic aromatic compound.

66. The co-crystal of claim 65, wherein the substituent is selected from C₁-C₄An organic acid moiety.

67. The co-crystal of claim 66, wherein the acid is C₂An acid moiety.

68. The crystalline compound of any one of claims 4-5, wherein the aromatic compound is substituted.

69. The crystalline compound of claim 68, wherein there is at least one substituent.

70. Crystallization of claim 69The compound, wherein the at least one substituent is selected from-OH, -NH₂Alkyl, -NO₂And a carbonyl-containing moiety.

71. The crystalline compound of claim 70, wherein said at least one substituent is an organic acid moiety.

72. The crystalline compound according to claim 71, wherein the organic acid is selected from C₁-C₄An organic acid moiety.

73. The crystalline compound according to claim 72, wherein said organic acid moiety is-COOH.

74. The crystalline compound of claim 70, wherein said at least one substituent is an-OH moiety.

75. The crystalline compound of claim 70, wherein said at least one substituent is selected from the group consisting of an ester and an alkyl moiety.

76. The crystalline compound according to claim 75, wherein the ester is selected from C₁-C₄And (3) an ester.

77. The crystalline compound of any one of claims 69-76, wherein the aromatic compound has two substituents.

78. The crystalline compound of any one of claims 69-76, wherein the aromatic compound has three substituents.

79. The crystalline compound of any one of claims 69-76, wherein the aromatic compound has four substituents.

80. The crystalline compound of claim 77, wherein there are two substituents, and each substituentIndependently selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial.

81. The crystalline compound of claim 80, wherein the first substituent is an organic acid and the second substituent is selected from the group consisting of-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial.

82. The crystalline compound of claim 81, wherein the second substituent is-NH ₂And (4) partial.

83. The crystalline compound of claim 80, wherein said-NH₂Moieties and the organic acid moieties are ortho to each other.

84. The crystalline compound of claim 80, wherein said-NH₂Moieties and the organic acid moiety are meta to each other.

85. The crystalline compound of claim 80, wherein said-NH₂Moieties and the organic acid moiety are para to each other.

86. The crystalline compound of claim 81, wherein the second substituent is-NO₂And (4) partial.

87. The crystalline compound of claim 86, wherein said-NO₂Moieties and the organic acid moieties are ortho to each other.

88. The crystalline compound of claim 86, wherein said-NO₂Moieties and the organic acid moiety are meta to each other.

89. The crystalline compound of claim 86, wherein said-NO₂Moieties and the organic acid moiety are para to each other.

90. The crystalline compound of claim 81, wherein the second substituent is an-OH moiety.

91. The crystalline compound of claim 90, wherein the-OH moiety and the organic acid moiety are ortho to each other.

92. The crystalline compound of claim 90, wherein the-OH moiety and the organic acid moiety are meta to each other.

93. The crystalline compound of claim 90, wherein the-OH moiety and the organic acid moiety are para to each other.

94. The crystalline compound of claim 81, wherein the second substituent is an alkyl moiety.

95. The crystalline compound of claim 94, wherein the alkyl moiety and the organic acid moiety are ortho to each other.

96. The crystalline compound of claim 94, wherein the alkyl moiety and the organic acid moiety are meta to each other.

97. The crystalline compound of claim 94, wherein the alkyl moiety and the organic acid moiety are para to each other.

98. The crystalline compound of claim 81, wherein the second substituent is an organic acid moiety.

99. The crystalline compound of claim 98, wherein two organic acid moieties are ortho to each other.

100. The crystalline compound of claim 98, wherein two organic acid moieties are meta to each other.

101. The crystalline compound of claim 98, wherein two organic acid moieties are para to each other.

102. The crystalline compound of claim 81, wherein the second substituent is an ester moiety.

103. The crystalline compound of claim 102, wherein the ester moiety and the organic acid moiety are ortho to each other.

104. The crystalline compound of claim 102, wherein the ester moiety and the organic acid moiety are meta to each other.

105. The crystalline compound of claim 102, wherein the ester moiety and the organic acid moiety are para to each other.

106. The crystalline compound of any one of claims 77-78, wherein there are three substituents, and each substituent is independently selected from-OH, -NH₂Alkyl, organic acids, esters and-NO₂And (4) partial.

107. The crystalline compound of claim 106, wherein the first substituent is an-OH moiety.

108. The crystalline compound of claim 107, wherein the second substituent and the third substituent are-OH moieties.

109. The crystalline compound of claim 106, wherein the first substituent is an organic acid moiety.

110. The crystalline compound of claim 106, wherein the second substituent and the third substituent are organic acid moieties.

111. The crystalline compound according to any one of claims 109-110, wherein the organic acid moiety is-COOH.

112. The crystalline compound of any one of claims 77-79, wherein there are four substituents, and each substituent is independently selected from-OH, -NH ₂Alkyl, organic acids, esters and-NO₂And (4) partial.

113. The crystalline compound of claim 112, wherein the first substituent is an ester.

114. The crystalline compound of claim 113, wherein the ester is a methyl ester.

115. A crystalline compound according to claim 113 wherein the ester is an ethyl ester.

116. The crystalline compound of any one of claims 113-115, wherein the second substituent is an-OH moiety.

117. The crystalline compound of any one of claims 113-115, wherein the second substituent, the third substituent, and the fourth substituent are each an-OH moiety.

118. The crystalline compound of any one of claims 4-5, wherein the aromatic compound is polycyclic.

119. The crystalline compound of any one of claims 68-90, wherein the aromatic compound is polycyclic.

120. The crystalline compound of any one of claims 118-119, wherein polycyclic aromatic is two six-membered rings.

121. The crystalline compound of any one of claims 118-119, wherein polycyclic aromatic is one six-membered ring and one five-membered ring.

122. The crystalline compound of any one of claims 4-5 or 68-121, wherein the ring atoms of the aromatic compound are all carbon.

123. The crystalline compound of any one of claims 4-5 or 68-121, wherein at least one ring atom is not carbon.

124. The crystalline compound of claim 123, wherein at least one ring atom is nitrogen.

125. The crystalline compound of any one of claims 118-124, wherein there is one substituent on the polycyclic aromatic compound.

126. The crystalline compound of claim 125, wherein said substituent is selected from C₁-C₄An organic acid moiety.

127. The crystalline compound of claim 126, wherein the organic acid moiety is C₂And (4) acid.

128. A crystalline compound comprising fasorasitan and 4-aminobenzoic acid.

129. A crystalline compound according to claim 128, wherein the fasorracetam is R-fasorracetam.

130. Co-crystals of fasoracetam and 4-aminobenzoic acid.

A co-crystal of R-fasorasitan and 4-aminobenzoic acid.

132. The co-crystal of claim 130, wherein the stoichiometric ratio of fasorracetam to 4-aminobenzoic acid is about 1: 1.

133. the co-crystal of claim 130, wherein the molar ratio of fasorracetam to 4-aminobenzoic acid in the unit cell of the co-crystal is 1: 1.

134. The co-crystal of claim 131, wherein the stoichiometric ratio of R-fasoracetam to 4-aminobenzoic acid is about 1: 1.

135. the co-crystal of claim 131, wherein the molar ratio of R-fasoracetam to 4-aminobenzoic acid in the unit cell of the co-crystal is 1: 1.

136. the co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak, in terms of ° 2 Θ, at about 6.5.

137. The co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak, in terms of ° 2 Θ, at about 10.5.

138. The co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak, in terms of ° 2 Θ, at about 11.3.

139. The co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak, in terms of ° 2 Θ, at about 12.0.

140. The co-crystal of any one of claims 131 or 134-135, wherein the X-ray powder diffraction of the co-crystal comprises one or more peaks selected from peaks at about 6.5 ° 2 Θ, about 10.5 ° 2 Θ, about 11.3 ° 2 Θ, and about 12.0 ° 2 Θ.

141. The co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 6.5 ° 2 Θ, about 10.5 ° 2 Θ, about 11.3 ° 2 Θ, about 12.0 ° 2 Θ, about 13.4 ° 2 Θ, about 13.7 ° 2 Θ, about 17.4 ° 2 Θ, about 18.1 ° 2 Θ, about 18.7 ° 2 Θ, about 19.6 ° 2 Θ, about 20.6 ° 2 Θ, about 21.1 ° 2 Θ, about 21.4 ° 2 Θ, about 22.8 ° 2 Θ, about 23.2 ° 2 Θ, and about 23.7 ° 2 Θ.

142. The co-crystal of any one of claims 131, 134-135, wherein the melting temperature of the co-crystal is about 114 ℃.

143. The co-crystal of claim 142, wherein the onset melting temperature is measured by differential scanning calorimetry.

144. The co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 6.5 ° 2 Θ, and an onset melting temperature of about 114 ℃.

145. The co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 10.5 ° 2 Θ, and an onset melting temperature of about 114 ℃.

146. The co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 11.3 ° 2 Θ, and an onset melting temperature of about 114 ℃.

147. The co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak at about 12.0 ° 2 Θ, and an onset melting temperature of about 114 ℃.

148. The co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks at 6.5 ° 2 Θ, about 10.5 ° 2 Θ, about 11.3 ° 2 Θ, or about 12.0 ° 2 Θ, and an onset melting temperature of about 114 ℃.

149. The co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 6.5 ° 2 Θ, about 10.5 ° 2 Θ, about 11.3 ° 2 Θ, about 12.0 ° 2 Θ, about 13.4 ° 2 Θ, about 13.7 ° 2 Θ, about 17.4 ° 2 Θ, about 18.1 ° 2 Θ, about 18.7 ° 2 Θ, about 19.6 ° 2 Θ, about 20.6 ° 2 Θ, about 21.1 ° 2 Θ, about 21.4 ° 2 Θ, about 22.8 ° 2 Θ, about 23.2 ° 2 Θ, and about 23.7 ° 2 Θ, and an initial melting temperature of the co-crystal is about 114 ℃.

150. The co-crystal of any one of claims 131 or 134-135, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 1.

151. The co-crystal of any one of claims 131 or 134-135, wherein the differential scanning calorimetry thermogram is substantially the same as figure 4.

152. The co-crystal of claim 130, wherein the fasorracetam is S-fasorracetam.

153. A pharmaceutical composition comprising a co-crystal of fasorasitan and 4-aminobenzoic acid and one or more pharmaceutically acceptable excipients.

154. The pharmaceutical composition of claim 153, wherein the fasorracetam is R-fasorracetam.

155. The pharmaceutical composition of claim 153, wherein the pharmaceutical composition has an X-ray powder diffraction pattern comprising a peak, in terms of 2 Θ, at about 6.5.

156. The pharmaceutical composition of claim 154, wherein an X-ray powder diffraction pattern comprises one or more peaks selected from peaks at about 6.5 ° 2 Θ, about 10.5 ° 2 Θ, about 11.3 ° 2 Θ, about 12.0 ° 2 Θ, about 13.4 ° 2 Θ, about 13.7 ° 2 Θ, about 17.4 ° 2 Θ, about 18.1 ° 2 Θ, about 18.7 ° 2 Θ, about 19.6 ° 2 Θ, about 20.6 ° 2 Θ, about 21.1 ° 2 Θ, about 21.4 ° 2 Θ, about 22.8 ° 2 Θ, about 23.2 ° 2 Θ, and about 23.7 ° 2 Θ.

157. The pharmaceutical composition of claim 154, wherein the R-fasoracetam co-crystal has an onset melting point temperature of about 114 ℃.

158. A crystalline compound comprising fasorasitan and trimesic acid.

159. The crystalline compound of claim 158, wherein the fasorracetam is R-fasorracetam.

160. Co-crystals of fasoracetam and trimesic acid.

161 eutectic of R-fasoracetam and trimesic acid.

162. The co-crystal of claim 160, wherein the stoichiometric ratio of fasoracetam to trimesic acid is about 1: 1.

163. the co-crystal of claim 160, wherein the molar ratio of fasorracetam to trimesic acid in the unit cell of the co-crystal is 1: 1.

164. the co-crystal of claim 161, wherein the stoichiometric ratio of R-fasoracetam to trimesic acid is about 1: 1.

165. the co-crystal of claim 161, wherein the molar ratio of R-fasoracetam to trimesic acid in the unit cell of the co-crystal is 1: 1.

166. the co-crystal of any one of claims 161 or 164-165, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak, in terms of ° 2 Θ, at about 9.7.

167. The co-crystal of any one of claims 161 or 164-165, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 9.7 ° 2 Θ, about 10.9 ° 2 Θ, about 11.4 ° 2 Θ, about 14.6 ° 2 Θ, about 16.5 ° 2 Θ, about 17.5 ° 2 Θ, about 18.6 ° 2 Θ, about 19.4 ° 2 Θ, about 19.8 ° 2 Θ, about 21.8 ° 2 Θ, about 23.5 ° 2 Θ, about 26.7 ° 2 Θ, and about 27.3 ° 2 Θ.

168. The co-crystal of any one of claims 161 or 164-165, wherein the initial melting temperature of the co-crystal is about 96 ℃.

169. The co-crystal of claim 168, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 9.7 ° 2 Θ, about 10.9 ° 2 Θ, about 11.4 ° 2 Θ, about 14.6 ° 2 Θ, about 16.5 ° 2 Θ, about 17.5 ° 2 Θ, about 18.6 ° 2 Θ, about 19.4 ° 2 Θ, about 19.8 ° 2 Θ, about 21.8 ° 2 Θ, about 23.5 ° 2 Θ, about 26.7 ° 2 Θ, and about 27.3 ° 2 Θ.

170. The co-crystal of any one of claims 161 or 164-165, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 51.

171. The co-crystal of any one of claims 161 or 164-165, wherein a DSC thermogram of the co-crystal is substantially the same as figure 54.

172. A crystalline compound comprising R-fasorasitan and R-ibuprofen.

A co-crystal of R-fasorasitan and R-ibuprofen.

174. The co-crystal of claim 173, wherein the stoichiometric ratio of R-fasoracetam to R-ibuprofen is about 1: 1.

175. the co-crystal of claim 173, wherein the molar ratio of R-fasoracetam to R-ibuprofen in the unit cell of the co-crystal is 1: 1.

176. The co-crystal of any one of claims 173-175, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.6 ° 2 Θ, about 10.5 ° 2 Θ, about 11.2 ° 2 Θ, about 12.3 ° 2 Θ, about 17.4 ° 2 Θ, about 20.1 ° 2 Θ, and about 20.6 ° 2 Θ.

177. The co-crystal of any one of claims 173-175, wherein the co-crystal has an onset melting temperature of about 115 ℃.

178. The co-crystal of claim 176, wherein the initial melting temperature of the co-crystal is about 115 ℃.

179. The co-crystal of any one of claims 173-175, having an X-ray powder diffraction pattern substantially the same as fig. 57.

180. The co-crystal of any one of claims 173-175, having a DSC thermogram substantially the same as figure 61.

181. A crystalline compound comprising fasorexiptan and phloroglucinol.

182. The crystalline compound of claim 181, wherein the fasorasitan is R-fasorasitan.

183. A monohydrate co-crystal of fasoracetam and phloroglucinol.

A monohydrate co-crystal of R-fasorasitan and phloroglucinol.

185. The co-crystal of claim 183, wherein fasorexiptan: phloroglucinol: the stoichiometric ratio of water is about 1: 1.

186. The co-crystal of claim 183, wherein in the unit cell of the co-crystal, the ratio of fasorracetam: phloroglucinol: the molar ratio of water is 1: 1: 1.

187. the co-crystal of claim 184, wherein the stoichiometric ratio of R-fasoracetam to phloroglucinol is from about 1: 1.

188. the co-crystal of claim 184, wherein the molar ratio of R-fasoracetam to phloroglucinol in the unit cell of the co-crystal is 1: 1.

189. the co-crystal of any one of claims 184 or 187-188, wherein an X-ray powder diffraction pattern of the co-crystal has one or more peaks selected from peaks at about 6.9 ° 2 Θ, about 10.3 ° 2 Θ, about 15.3 ° 2 Θ, about 16.2 ° 2 Θ, about 17.3 ° 2 Θ, about 21.6 ° 2 Θ, about 22.6 ° 2 Θ, and about 25.3 ° 2 Θ.

190. The co-crystal of any one of claims 184 or 187-188, having an onset melting temperature of about 58 ℃.

191. The co-crystal of claim 189, having an onset melting temperature of about 58 ℃.

192. The co-crystal of any one of claims 184 or 187-188, having an X-ray powder diffraction pattern substantially the same as figure 72.

193. A crystalline compound comprising fasorexiptan and methyl-3, 4, 5-trihydroxybenzoate.

194. A crystalline compound according to claim 193, wherein the fasorracetam is R-fasorracetam.

195. Eutectic of fasoracetam and methyl-3, 4, 5-trihydroxybenzoate monohydrate.

A monohydrate co-crystal of R-fasorasitan and methyl-3, 4, 5-trihydroxybenzoate.

197. The co-crystal of claim 195, wherein the stoichiometric ratio of fasorasitan to methyl-3, 4, 5-trihydroxybenzoate is about 1: 1.

198. the co-crystal of claim 195, wherein the molar ratio of fasorracetam to methyl-3, 4, 5-trihydroxybenzoate in the unit cell of the co-crystal is 1: 1.

199. the co-crystal of claim 196, wherein the stoichiometric ratio of R-fasoracetam to methyl-3, 4, 5-trihydroxybenzoate is about 1: 1.

200. the co-crystal of claim 196, wherein the molar ratio of R-fasorasitan to methyl-3, 4, 5-trihydroxybenzoate in the unit cell of the co-crystal is 1: 1.

201. the co-crystal of any one of claims 196 or 199-200, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.7 ° 2 Θ, about 10.6 ° 2 Θ, about 11.3 ° 2 Θ, about 12.7 ° 2 Θ, about 16.6 ° 2 Θ, about 18.9 ° 2 Θ, about 20.6 ° 2 Θ, about 24.3 ° 2 Θ, and about 25.0 ° 2 Θ.

202. The co-crystal of any one of claims 196 or 199-200, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 75.

203. A crystalline compound comprising fasoraferacetam and ethyl gallate.

204. The crystalline compound of claim 203, wherein the fasorracetam is R-fasorracetam.

205. Co-crystal of fasorasitan and ethyl gallate.

Eutectic of R-fasorasitan and ethyl gallate.

207. The co-crystal of claim 205, wherein the stoichiometric ratio of fasoraferacetam to ethyl gallate is about 1:1 or about 1: 2.

208. the co-crystal of claim 205, wherein in the unit cell of the co-crystal, the molar ratio of fasorracetam to ethyl gallate is 1:1 or 1: 2.

209. the co-crystal of claim 206, wherein the stoichiometric ratio of R-fasoracetam to ethyl gallate is about 1:1 or about 1: 2.

210. the co-crystal of claim 206, wherein the molar ratio of R-fasorasitan to ethyl gallate in the unit cell of the co-crystal is 1:1 or 1: 2.

211. the co-crystal of any one of claims 206 or 209-210, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.8 ° 2 Θ, about 11.3 ° 2 Θ, about 12.4 ° 2 Θ, about 15.5 ° 2 Θ, about 15.8 ° 2 Θ, about 18.2 ° 2 Θ, about 19.4 ° 2 Θ, about 22.0 ° 2 Θ, and about 24.8 ° 2 Θ, and

Wherein, in unit cell, the molar ratio of R-fasoracetam to ethyl gallate is 1:1, or

Wherein the stoichiometric ratio of R-fasorasitan to ethyl gallate is about 1: 1.

212. the co-crystal of claim 211, wherein the molar ratio of R-fasoracetam to ethyl gallate in the unit cell is 1: 1.

213. the co-crystal of claim 211, wherein the initial melting temperature of the co-crystal is about 112 ℃.

214. The co-crystal of claim 212, wherein the co-crystal has an onset melting point temperature of about 112 ℃.

215. The co-crystal of claim 206, wherein the X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.8 ° 2 Θ, about 7.2 ° 2 Θ, about 14.8 ° 2 Θ, about 20.4 ° 2 Θ, about 21.9 ° 2 Θ, and about 23.5 ° 2 Θ, wherein in the unit cell of the co-crystal, the molar ratio of R-fasoracetam to ethyl gallate is 1: 2.

216. the co-crystal of claim 206, wherein the X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.8 ° 2 Θ, about 7.2 ° 2 Θ, about 14.8 ° 2 Θ, about 20.4 ° 2 Θ, about 21.9 ° 2 Θ, and about 23.5 ° 2 Θ, wherein the stoichiometric ratio of R-fasoracetam to ethyl gallate is about 1: 2.

217. A dihydrate co-crystal wherein the stoichiometric ratio of fasorasitan to ethyl gallate is about 1: 2.

218. a dihydrate co-crystal, wherein, in the unit cell of the co-crystal, the molar ratio of fasoracetam to ethyl gallate is 1: 2.

219. the dihydrate eutectic of any of claims 217-218, wherein the X-ray powder diffraction pattern of the eutectic comprises one or more peaks selected from peaks at about 8.8 ° 2 Θ, about 11.2 ° 2 Θ, about 19.4 ° 2 Θ, about 19.9 ° 2 Θ, and about 24.1 ° 2 Θ.

220. The co-crystal of any one of claims 217-219, wherein the co-crystal has an onset melting temperature of about 106 ℃ as measured by DSC.

221. The co-crystal of any one of claims 206 or 209-210, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 79.

222. The co-crystal of any one of claims 206 or 209-210, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 86.

223. The co-crystal of any one of claims 217-218, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 88.

224. The co-crystal of any one of claims 217-218, wherein the fasorracetam is R-fasorracetam.

225. A crystalline compound comprising fasoraferacetam and phthalic acid.

226. A crystalline compound according to claim 225, wherein the fasorracetam is R-fasorracetam.

227. Eutectic of fasorasitan and phthalic acid.

A co-crystal of R-fasorasitan and phthalic acid.

229. The co-crystal of claim 227, wherein the stoichiometric ratio of fasorexiptan to phthalic acid is about 1: 1.

230. the co-crystal of claim 227, wherein the molar ratio of fasorracetam to phthalic acid in the unit cell of the co-crystal is 1: 1.

231. the co-crystal of claim 228, wherein the stoichiometric ratio of R-fasoracetam to phthalic acid is about 1: 1.

232. the co-crystal of claim 228, wherein the molar ratio of R-fasoracetam to phthalic acid in the unit cell of the co-crystal is 1: 1.

233. the co-crystal of any one of claims 228 or 231-232, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 6.1 ° 2 Θ, about 12.4 ° 2 Θ, about 15.1 ° 2 Θ, about 15.8 ° 2 Θ, about 18.1 ° 2 Θ, about 19.9 ° 2 Θ, and about 23.3 ° 2 Θ.

234. The co-crystal of any one of claims 228 or 231-232, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 64.

235. A crystalline compound comprising fasoraferacetam and 6-hydroxy-2-naphthoic acid.

236. A crystalline compound according to claim 235, wherein the fasorracetam is R-fasorracetam.

237. Eutectic of fasorasitan and 6-hydroxy-2-naphthoic acid.

A co-crystal of R-fasorasitan and 6-hydroxy-2-naphthoic acid.

239. The co-crystal of claim 238, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak, in terms of ° 2 Θ, at about 11.2.

240. The co-crystal of claim 238, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 11.2 ° 2 Θ, about 14.9 ° 2 Θ, about 15.7 ° 2 Θ, about 20.1 ° 2 Θ, about 21.1 ° 2 Θ, about 23.6 ° 2 Θ, about 24.1 ° 2 Θ, about 25.0 ° 2 Θ, and about 25.5 ° 2 Θ.

241. The co-crystal of any one of claims 238-240, wherein the initial melting temperature of the co-crystal is about 120 ℃.

242. The co-crystal of claim 238 or 241, wherein an X-ray powder diffraction pattern of the co-crystal is substantially the same as figure 93.

243. The co-crystal of any one of claims 238-240 or 242, wherein the DSC thermogram of the co-crystal is substantially the same as figure 97.

244. A crystalline compound comprising fasorasitan and 4-nitrobenzoic acid.

245. The crystalline compound of claim 244, wherein the fasorracetam is R-fasorracetam.

246. Co-crystal of fasoracetam and 4-nitrobenzoic acid.

A co-crystal of R-fasorasitan and 4-nitrobenzoic acid.

248. The co-crystal of claim 246, wherein the stoichiometric ratio of fasorracetam to 4-nitrobenzoic acid is about 1: 2.

249. the co-crystal of claim 246, wherein the molar ratio of fasorracetam to 4-nitrobenzoic acid in the unit cell of the co-crystal is 1: 2.

250. the co-crystal of claim 247, wherein the stoichiometric ratio of R-fasoracetam to 4-nitrobenzoic acid is about 1: 2.

251. the co-crystal of claim 247, wherein the molar ratio of R-fasoracetam to 4-nitrobenzoic acid in the unit cell of the co-crystal is 1: 2.

252. the eutectic of any one of claims 247 or 250, 251, wherein the X-ray powder diffraction pattern of the eutectic comprises one or more peaks selected from peaks at about 6.5 ° 2 Θ, about 6.7 ° 2 Θ, about 8.9 ° 2 Θ, about 14.5 ° 2 Θ, about 15.6 ° 2 Θ, about 17.9 ° 2 Θ, about 18.6 ° 2 Θ, about 19.8 ° 2 Θ, about 23.4 ° 2 Θ, and about 26.4 ° 2 Θ.

253. The co-crystal of any one of claims 247 or 250 and 251, wherein the X-ray powder diffraction pattern of the co-crystal is substantially the same as that of plot 100.

254. The eutectic of any one of claims 247 or 250 and 253, wherein the onset melting temperature of the eutectic is about 146 ℃.

255. The co-crystal of any one of claims 247 or 250 and 253, wherein the DSC thermogram of the co-crystal is substantially the same as figure 105.

256. A crystalline compound comprising fasorasiracetam and 2-indole-3-acetic acid.

257. The crystalline compound of claim 256, wherein the fasorracetam is R-fasorracetam.

258. Co-crystals of fasorasitan and 2-indole-3-acetic acid.

A co-crystal of R-fasorasitan and 2-indole-3-acetic acid.

260. The co-crystal of claim 259, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak, in terms of ° 2 Θ, at about 11.8.

261. The co-crystal of claim 259, wherein an X-ray powder diffraction pattern of the co-crystal comprises one or more peaks selected from peaks at about 5.3 ° 2 Θ, about 7.9 ° 2 Θ, about 10.7 ° 2 Θ, about 11.8 ° 2 Θ, about 14.7 ° 2 Θ, about 15.8 ° 2 Θ, about 18.0 ° 2 Θ, about 21.9 ° 2 Θ, about 23.1 ° 2 Θ, and about 23.5 ° 2 Θ.

262. The eutectic of any one of claims 259-261, wherein the eutectic has an onset melting temperature of about 69 ℃.

263. The co-crystal of claim 259, wherein the X-ray powder diffraction pattern of the co-crystal is substantially the same as pattern 107.

264. The co-crystal of any one of claims 259-261 or 263, wherein the DSC thermogram of the co-crystal is substantially the same as figure 111.

265. The co-crystal of claim 1, wherein the co-crystal former is non-aromatic and comprises a compound selected from-NH₂、-NO₂Organic acids such as-COOH, -C (═ O) -X, -C (═ O) -OR₁At least one moiety of (1), wherein R₁Is an alkyl group and X is a nitrogen-containing moiety.

266. The co-crystal of claim 266, wherein R₁Is C₁To C₁₂An alkyl group.

267. The co-crystal of claim 265 or 266, wherein the non-aromatic co-crystal former comprises at least one NH₂。

268. The method as set forth in any one of claims 265 to 267The co-crystal of (1), wherein the non-aromatic co-crystal former comprises two NH groups₂And (4) partial.

269. The co-crystal of any of claims 265-268, wherein the fasorracetam is R-fasorracetam.

270. The co-crystal of claim 1, wherein the co-crystal former is non-aromatic and comprises at least one-C (O) NR ₂R₃Moiety wherein R₂And R₃Independently selected from H, alkyl, substituted alkyl and C₁To C₅An alcohol.

271. The co-crystal of claim 270, wherein the co-crystal former comprises one of-c (o) NR₂R₃And (4) partial.

272. The co-crystal of any of claims 270-271, wherein alkyl and substituted alkyl each independently comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbons.

273. The co-crystal of claim 272, wherein substituted alkyl is substituted with at least one of a halogen or a nitrile.

274. The co-crystal of claim 273, wherein the halogen is bromine.

275. The co-crystal of any one of claims 270-274, wherein the alcohol is C₂An alcohol.

276. The co-crystal of any one of claims 270-274, wherein the alkyl is C₁₁An alkyl group.

277. The co-crystal of claim 1, wherein the co-crystal former is non-aromatic and comprises at least one-c (o) NX moiety, wherein X is ═ N-R₄Which isIn R₄Is a carbonyl containing moiety.

278. The co-crystal of claim 277, wherein the carbonyl-containing moiety is an amide.

279. The co-crystal of any one of claims 270-278, wherein the fasorracetam is R-fasorracetam.

280. A crystalline compound comprising fasoraferacetam and urea.

281. A crystalline compound according to claim 280, wherein the fasorracetam is R-fasorracetam.

282. Eutectic of fasorasitan and urea.

A co-crystal of R-fasorasitan and urea.

284. The co-crystal of claim 282, wherein the stoichiometric ratio of fasoraferacetam to urea is about 1: 1.

285. the co-crystal of claim 282, wherein the molar ratio of fasorracetam to urea in the unit cell of the co-crystal is 1: 1.

286. the co-crystal of claim 283, wherein the stoichiometric ratio of R-fasoracetam to urea is about 1: 1.

287. the co-crystal of claim 283, wherein the molar ratio of R-fasoracetam to urea in the unit cell of the co-crystal is 1: 1.

288. the eutectic of any one of claims 283 or 286-287, wherein the X-ray powder diffraction pattern of the eutectic comprises a peak at about 10.4 ° 2 Θ.

289. The eutectic of any one of claims 283 or 286-287, wherein the X-ray powder diffraction pattern of the eutectic comprises a peak at about 14.0 ° 2 Θ or about 14.1 ° 2 Θ.

290. The eutectic of any one of claims 283 or 286-287, wherein the X-ray powder diffraction pattern of the eutectic comprises a peak at about 10.8 ° 2 Θ.

Form A of a co-crystal of R-fasorasitan and urea.

292. A co-crystal of R-fasorracetam and urea type a according to any one of claims 282-290.

293. The co-crystal of claim 291, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak, in terms of ° 2 Θ, at about 12.2.

294. The co-crystal of claim 291, wherein an X-ray powder diffraction pattern of the co-crystal comprises a peak, in terms of ° 2 Θ, at about 16.1.

295. The co-crystal of claim 291, wherein an X-ray powder diffraction pattern of the co-crystal comprises one peak at about 12.2 ° Θ, and one or more peaks selected from peaks at about 10.4 ° 2 Θ, about 10.8 ° 2 Θ, about 14.1 ° 2 Θ, about 16.1 ° 2 Θ, about 18.9 ° 2 Θ, about 22.3 ° 2 Θ, and about 22.9 ° 2 Θ.

296. The co-crystal of claim 291, wherein an X-ray powder diffraction pattern of the co-crystal comprises one peak at about 16.1 ° 2 Θ, and one or more peaks selected from peaks at about 10.4 ° 2 Θ, about 10.8 ° 2 Θ, about 12.2 ° 2 Θ, about 14.1 ° 2 Θ, about 18.9 ° 2 Θ, about 22.3 ° 2 Θ, and about 22.9 ° 2 Θ.

297. The co-crystal of claim 291, having an X-ray powder diffraction pattern substantially the same as figure 44.

298. The eutectic of any one of claims 291 or 293-wall 297, wherein the onset of melting of the eutectic is about 91 ℃.

299. The co-crystal of claim 298, wherein the melting temperature is measured with DSC.

300. The co-crystal of claim 299, wherein a DSC thermogram of the co-crystal is substantially the same as figure 47.

301. The co-crystal of claim 282, wherein the fasorracetam is S-fasorracetam.

302. A pharmaceutical composition comprising a co-crystal of fasoraferacetam and urea and one or more pharmaceutically acceptable excipients.

303. The pharmaceutical composition of claim 302, wherein the fasorracetam is R-fasorracetam.

304. The pharmaceutical composition of any one of claims 302-303, wherein the X-ray powder diffraction pattern of the pharmaceutical composition comprises a peak, in terms of 2 Θ, at about 10.4 °.

305. The pharmaceutical composition of any one of claims 302-304, wherein the composition comprises the co-crystal of claim 295 or 296.

306. The pharmaceutical composition as set forth in any one of claims 302-305, wherein the R-fasoracetam co-crystal has an initial melting point temperature of about 91 ℃.

Form B of a co-crystal of R-fasorasitan and urea.

308. The co-crystal of claim 307, wherein the stoichiometry of R-fasorasitan and urea is about 1: 1.

309. The co-crystal of claim 307, wherein the molar ratio of R-fasorracetam to urea in the unit cell of the co-crystal is 1: 1.

310. the eutectic of any one of claims 307-309, wherein an X-ray powder diffraction pattern of the eutectic comprises a peak at about 11.4 ° 2 Θ.

311. The eutectic of any one of claims 307-309, wherein an X-ray powder diffraction pattern of the eutectic comprises a peak at about 17.5 ° 2 Θ.

312. The eutectic of any one of claims 307-309, wherein an X-ray powder diffraction pattern of the eutectic comprises at least two peaks selected from peaks at about 14.0 ° 2 Θ, about 14.5 ° 2 Θ, and about 14.9 ° 2 Θ.

313. The eutectic of any one of claims 307-309, wherein an X-ray powder diffraction pattern of the eutectic comprises peaks at about 14.5 ° 2 Θ and about 14.9 ° 2 Θ.

314. The eutectic of any one of claims 307-309, wherein an X-ray powder diffraction pattern of the eutectic comprises a peak at about 14.5 ° 2 Θ.

315. The eutectic of any one of claims 307-309, wherein an X-ray powder diffraction pattern of the eutectic comprises a peak at about 14.9 ° 2 Θ.

316. The eutectic of any one of claims 307-309, wherein an X-ray powder diffraction pattern of the eutectic comprises one or more peaks selected from peaks at about 11.4 ° 2 Θ, about 14.0 ° 2 Θ, about 14.5 ° 2 Θ, about 14.9 ° 2 Θ, and about 17.5 ° 2 Θ.

317. The eutectic of any one of claims 307-309, wherein an X-ray powder diffraction pattern of the eutectic comprises one peak at about 11.4 ° 2 Θ, and one or more peaks selected from the group consisting of peaks at about 10.4 ° 2 Θ, about 14.0 ° 2 Θ, about 14.5 ° 2 Θ, about 14.9 ° 2 Θ, about 17.5 ° 2 Θ, about 18.4 ° 2 Θ, about 18.7 ° 2 Θ, about 19.4 ° 2 Θ, about 20.1 ° 2 Θ, and about 21.1 ° 2 Θ.

318. The eutectic of any one of claims 307-317, wherein the initial melting point of the eutectic is about 102 ℃.

319. The co-crystal of claim 318, wherein the onset melting point is determined by DSC.

320. The eutectic of any one of claims 307-309 or 318-319, wherein the X-ray powder diffraction pattern of the eutectic is substantially the same as figure 37.

321. The co-crystal of any one of claims 307-317 or 320, wherein a differential scanning calorimetry thermogram of the co-crystal is substantially the same as figure 40.

322. A pharmaceutical composition comprising a form B co-crystal of fasoraferacetam and urea and one or more pharmaceutically acceptable excipients.

323. A pharmaceutical composition according to claim 322, wherein the fasorracetam is R-fasorracetam.

324. The pharmaceutical composition of any one of claims 322-323, wherein the X-ray powder diffraction pattern of the pharmaceutical composition comprises a peak, in terms of 2 Θ, at about 11.4 °.

325. The pharmaceutical composition of any one of claims 322-323, wherein the composition has an X-ray powder diffraction pattern comprising one or more peaks, wherein the X-ray powder diffraction pattern of the co-crystal comprises one peak at about 11.4 ° 2 Θ, and one or more peaks selected from the group consisting of peaks at about 10.4 ° 2 Θ, about 14.0 ° 2 Θ, about 14.5 ° 2 Θ, about 14.9 ° 2 Θ, about 17.5 ° 2 Θ, about 18.4 ° 2 Θ, about 18.7 ° 2 Θ, about 19.4 ° 2 Θ, about 20.1 ° 2 Θ, and about 21.1 ° 2 Θ.

326. The pharmaceutical composition of any one of claims 322-325, wherein the R-fasoracetam co-crystal has an onset melting temperature of about 102 ℃.

327. The co-crystal of claim 1, wherein the co-crystal former comprises at least one carboxylic acid functional group.

328. The co-crystal of claim 327, wherein the fasoracetam forms a synthon of formula II with the carboxylic acid functional group of the co-crystal former

329. The co-crystal of claim 1, wherein the co-crystal former comprises a material selected from the group consisting of oxygen, nitrogen, -NH, alkyl, and- (O) COR ₅At least one functional group of (1), wherein R₅Selected from hydrogen or alkyl, e.g. C₁To C₅An alkyl group.

330. The co-crystal of claim 329, wherein the fasoracetam and the co-crystal former form a synthon of formula III

331. The co-crystal of claim 330, wherein Y is selected from the group consisting of oxygen, nitrogen, -NH, and- (O) COR₅Wherein R is₅Selected from substituted or unsubstituted alkyl groups and substituted or unsubstituted aryl groups.

332. The co-crystal of claim 331, wherein Y is- (O) COR₅Wherein R is₅Selected from substituted or unsubstituted alkyl groups and substituted or unsubstituted aryl groups.

333. The co-crystal of any one of claims 7-22, 26, 30, 34, 42, 46, or 49-57, wherein the aromatic compound comprises an aromatic ring fused to a non-aromatic cyclic moiety.

334. The co-crystal of claim 333, wherein at least one non-aromatic cyclic moiety is partially saturated.

335. The co-crystal of claim 333, wherein there are at least two non-aromatic cyclic moieties.

336. The co-crystal of claim 333, wherein at least one non-aromatic cyclic moiety does not share a ring atom with an aromatic moiety.

337. A pharmaceutical composition comprising the crystalline compound of any one of claims 4-6, 68-129, 158-159, 172, 181-182, 193-194, 203-204, 225-226, 235-236, 244-245, 256-257 or 280-281, or the eutectic of any one of claims 1-3, 7-67, 130-152, 160-171, 173-180, 183-192, 195-202, 205-224, 227-234, 237-243, 246-255, 258-279, 282-301, 307-321 or 327-336, and one or more pharmaceutically acceptable excipients.

338. The crystalline compound of any one of claims 4-6, 68-129, 158-159, 172, 181-182, 193-194, 203-204, 225-226, 235-236, 244-245, 256-257 or 280-281, the pharmaceutical composition of any one of claims 1-3, 7-67, 130-152, 160-171, 173-180, 183-192, 195-202, 205-224, 227-234, 237-243, 246-255, 258-279, 282-301, 307-321 or 327-336, or the pharmaceutical composition of any one of claims 153-157, 302-306, 322-326 or 337, for treating attention deficit hyperactivity disorder in a human subject in need thereof.

339. The use of claim 338, wherein the subject has at least one Copy Number Variation (CNV) in a metabotropic glutamate receptor (mGluR) network gene.

340. The co-crystal of any one of claims 52-57, wherein at least one substituent is an organic acid moiety.

341. The co-crystal of claim 340, wherein the organic acid is a-COOH moiety.

342. The pharmaceutical composition of claim 302, wherein the cocrystal of R-fasorracetam and urea is selected from any one of claims 283-300 or 307-321.

343. A method for preparing R-fasorasiracetam B: a method of co-crystallizing urea, comprising:

Mixing R-fasorasitan with urea in a suitable solvent to form a solution, wherein the molar amount of urea to R-fasorasitan is from about 0.7 to about 1.2;

cooling the solution to form R-fasorasitan form B: eutectic of urea eutectic.

344. The process of claim 343, wherein the R-fasorasitan is selected from the group consisting of: r-fasorasiracetam type I, R-fasorasiracetam type II, amorphous forms of R-fasorasiracetam, anhydrous R-fasorasiracetam, and mixtures of R-fasorasiracetam forms.

345. A process according to claim 344, wherein the R-fasoracetam is form I.

346. The process as set forth in claim 343-345 wherein the suitable solvent is selected from the group consisting of ethyl acetate and isopropyl acetate.

347. The process of claim 346 wherein the suitable solvent is ethyl acetate.

348. A process as set forth in claim 345 wherein the ratio of the suitable solvent to R-fasoracetam per gram of form I is from about 2.5ml to about 6 ml.

349. The process of claim 348, wherein the ratio of the suitable solvent to R-fasoracetam per gram of form I is about 3.0ml to about 5.0 ml.

350. The process of claim 348, wherein the ratio of the suitable solvent to R-fasoracetam per gram of form I is about 3.8ml to about 4.6 ml.

351. The method as recited in claim 348-350, wherein the suitable solvent comprises ethyl acetate.

352. The method of claim 343-351 wherein the temperature of the solution is between about 10 ℃ and 15 ℃.

353. The method of claim 343-351 wherein the temperature of the solution is about 15-20 ℃.

354. The method of claim 343-351 wherein the temperature of the solution is between about 20 ℃ and 25 ℃.

355. The method of claim 343-351 wherein the temperature of the solution is about 25-30 ℃.

356. The method of claim 343-351 wherein the temperature of the solution is between about 30 ℃ and 35 ℃.

357. The method of claim 343-351 wherein the temperature of the solution is between about 35 ℃ and 40 ℃.

358. The method of claim 343-351 wherein the temperature of the solution is about 40-45 ℃.

359. The method of claim 343-351 wherein the temperature of the solution is about 45-50 ℃.

360. The method of claim 343-351 wherein the temperature of the solution is about 50-55 ℃.

361. The method of claim 343-351 wherein the temperature of the solution is about 55-60 ℃.

362. The method of claim 343-351 wherein the temperature of the solution is about 60-65 ℃.

363. The method of claim 343-351 wherein the temperature of the solution is about 65-70 ℃.

364. The method as set forth in claim 343-363 wherein the urea is added stepwise.

365. The method as set forth in claim 343-363 wherein the urea is added all at once.

366. The process as set forth in claim 343-365 wherein the molar amount of urea and R-fasoracetam is about 0.70, about 0.71, about 0.72, about 0.73, about 0.74, about 0.75, about 0.76, about 0.77, about 0.78, about 0.79, about 0.80, about 0.81, about 0.82, about 0.83, about 0.84, about 0.85, about 0.86, about 0.87, about 0.88, about 0.89, about 0.90, about 0.91, about 0.92, about 0.93, about 0.94, about 0.95, about 0.96, about 0.97, about 0.98, about 0.99, about 1.0, about 1.1 or about 1.2.

367. The process as set forth in claim 343-365 wherein the molar amount of urea to R-fasoracetam is from about 0.95 to about 1.0.

368. The process as set forth in claim 343-367, wherein the compound of R-fasorasitan form B: eutectic seeds of urea eutectic are added to the solution.

369. The process as set forth in claim 343-368, wherein the resulting R-fasorasitan form B is washed after cooling: eutectic of urea eutectic.

370. The process as set forth in claim 343-369, wherein the resulting R-fasorasitan form B: and (4) drying the eutectic of the urea eutectic.

371. R-fasorasiracetam form B prepared by the process of any of claims 343-370: and (4) urea eutectic crystal.

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